Monoclonal antibody (mAb) development has progressed in many fields, especially oncology, but remains limited in infectious diseases. Life-threatening infections like SARS-CoV-2 and invasive Streptococcus pyogenes (e.g., necrotizing soft tissue infections with over 20% mortality) could benefit from mAb therapy. Most SARS-CoV-2 antibodies are expressed as the IgG1 subclass, focusing on neutralizing the virus, with little focus on enhancing immune system interaction. Only one protective monoclonal antibody has been described for Streptococcus pyogenes (group A streptococcus, GAS). This thesis explores improving the therapeutic potential of mAbs against both types of pathogens through Fc-engineering. In Paper I, we found that non-neutralizing antibodies protect mice from a lethal infection with the original Wuhan strain of SARS-CoV-2. While neutralizing RBD antibodies have been shown to protect animals, this is the first report of a non-neutralizing RBD antibody providing protection. The mechanism was via Fc-mediated functions like phagocytosis, which we could enhance further by switching the constant domain from IgG1 to IgG3. A cocktail of IgG3 antibodies produced the strongest response. We also discovered that the constant domain affects antigen binding, challenging the belief that the variable and constant domains are independent. Due to mutations in the SARS-CoV-2 spike protein, most neutralizing antibodies become ineffective. In Paper III, we show that one of our non-neutralizing antibodies remains functional and binds after 4 years of mutations, making it potentially a more durable therapeutic option than neutralizing antibodies. The non-neutralizing antibody improved clinical symptoms in mice infected with the highly mutated JN.1 variant of SARS-CoV-2, which showed surprisingly low virulence in this model - providing insight into the viral evolution. In Paper II, we generated all four human subclasses of the protective anti-M monoclonal antibody against Streptococcus pyogenes. We found that the IgG3 version had reduced binding to the antigen, but surprisingly exhibited much higher opsonophagocytic activity than IgG1. This was likely due to its longer hinge domain, which provided greater flexibility, as supported by molecular dynamics simulations. These simulations showed differences in hydrogen bond and salt-bridge interactions between the M protein and the IgG1 and IgG3 subclasses, potentially explaining the reduced binding of IgG3. We further demonstrated the importance of the hinge domain by creating IgG1-IgG3 hybrid subclasses. The IgGh47 version, with a 47 amino acid IgG3 hinge, showed an even stronger opsonic function than both IgG1 and IgG3. In a mouse model of severe GAS infection, only IgGh47 protected mice, while the natural subclasses did not. This enhanced function was transferable to different clinical isolates and even SARS-CoV-2 spike antibodies. In Paper IV, IgGh47 versions of anti-spike antibodies improved phagocytosis against mutated SARS-CoV-2 variants and other Betacoronaviruses, like SARS-CoV and MERS-CoV. These antibodies also showed unexpectedly high affinity for Fc receptors, unlike their IgG1 parents. Overall, this thesis shows that the IgGh47 subclass is a promising backbone for enhancing non-neutralizing protective functions against Streptococcus pyogenes, SARS-CoV-2, and potentially other Betacoronaviruses. Additionally, the altered antigen-binding observed in Papers I-II, along with the molecular dynamics simulations, challenges the traditional view of antibody variable and constant domain independence.