ABSTRACT Excessive complement activation causes many diseases especially hematologic diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), in which patient erythrocytes are attacked by activated complement, causing extravascular and intravascular hemolysis, thus anemia, thrombosis, and other life-threatening complications. Several complement inhibitors have been approved by the FDA for treating these disorders with limited success, thus there is still a clinical demand for better complement-targeted therapeutics. In pilot studies, we have developed a novel nanobody-based complement inhibitor and demonstrated its potential in treating complement-mediated hematologic diseases. In this project, we will develop additional novel complement inhibitors and thoroughly characterize them (R61 Phase), then examine the lead candidate in preclinical models of PNH and AIHA for its treatment efficacies and pharmacokinetics profiles (R33 Phase). This project, if successful, will identify a promising first-in-class complement inhibitor for further clinical development into a much-needed new drug for patients with complement-mediated diseases such as PNH and AIHA.