Project Summary The Coronavirus Disease 2019 (COVID-19) pandemic is currently gripping the world without a known cure or prevention. Aside from the health consequences, the necessary decrease in human activity has resulted in economic losses without modern precedent, especially in the developing world where health care and sanitation were not sufficient even prior to the pandemic. Innumerable efforts are being undertaken to develop vaccines to SARS-CoV-2 and it is likely that antibodies will be essential for protection. COVID-19 antibody therapy in the form of polyclonal plasma from convalescent individuals is currently being explored as a therapeutic option and has been granted an emergency use authorization (EUA) by the FDA. Monoclonal antibodies may prove to be particularly useful in preventing SARS-CoV-2 infection in populations who may not mount protective immune responses to vaccination (e.g. advanced age, immunocompromise) and for post-exposure prophylaxis in individuals at high risk to develop severe COVID-19. C135 and C144 are recombinant, fully human mAbs that specifically bind SARS-CoV-2 spike protein receptor binding domain (RBD) and exhibit exceptional neutralizing activity in vitro against SARS-CoV-2. Two one-amino acid mutations have been introduced to prolong half-life and allow dose sparing. The C135-LS and C144-LS combination has shown remarkable activity in both prophylaxis and therapy experiments in several relevant animal models in both prophylaxis and treatment experiments. These preclinical data support the clinical evahe from SARS-CoV-2 and accelerate viral clearance and disease resolution in SARS-CoV-2-infected individuals. The proposed study is a first-in-human, open label, single dose, dose-escalation phase 1 trial to evaluate the safety and pharmacokinetics of the C135-LS and C144-LS combination in healthy volunteers.