Medical Biology - Theses

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    Development of antibody therapeutics for deadly infectious diseases: malaria and COVID-19
    Chan, Li Jin ( 2021)
    Monoclonal antibodies are one of the most powerful drugs used in the treatment of human diseases, particularly for autoimmune diseases and cancer. The development of therapeutic antibodies to combat infectious diseases is expanding, with successful treatments available against viral diseases such as COVID-19, Ebola virus, HIV and RSV. The use of monoclonal antibodies complements vaccines by providing immediate protection, preventing disease in immunocompromised people and in containing emerging disease outbreaks. In this thesis, I aimed to characterise neutralizing antibodies against two of the deadliest infectious diseases that affect global populations, malaria and COVID-19. The growth and replication of both these pathogens are critically dependent on their entry into host cells. Neutralizing antibodies that block pathogen entry into host cells can prevent infection and reduce severe disease. Plasmodium vivax is the most widespread relapsing human malaria, which invades reticulocytes through the critical interaction between P. vivax reticulocyte binding protein 2b (PvRBP2b) and human Transferrin receptor 1 (TfR1). I identified TfR1 residues that are critical for complex formation with PvRBP2b. In addition, I characterised naturally acquired human monoclonal antibodies to PvRBP2b, and using structural biology, revealed the epitopes of eight high affinity inhibitory antibodies that block complex formation through different mechanisms. The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which utilizes its spike protein to engage human angiotensin-converting enzyme 2 (ACE2) for host cell entry. I performed deep mutational scanning on a lead neutralising nanobody against SARS-CoV-2 to improve its potency, stability and affinity. These structural studies increase our understanding of host-pathogen interactions and the antibodies that block them, which can inform the development of antibody therapeutics or vaccines.