Development of Monoclonal Antibodies to the Alternative Complement Pathway-Specific Protein Activated Factor B (fBb)as Therapeutics for PNH

Project Summary Abstract The goal of this project at True North Therapeutics is to develop monoclonal antibodies that specifically inhibit the alternative pathway of complement AP Inhibition of the AP at the level of the upstream amplification loop is designed to be an improvement over the current standard of care for diseases such as paroxysmal nocturnal hemoglobinuria PNH The current anti C therapeutic eculizumab does abolish intravascular hemolysis in almost all PNH patients eventually resulting in a substantial clinical benefit in terms of symptoms and acute disease manifestations Nevertheless the hematological benefit is extremely heterogeneous since about one third of patients still remain transfusion dependent or severely anemic By inhibiting the accumulation of the upstream C split products that serve as opsonins our goal is to prevent the destruction of RBCs via phagocytosis by cells of the mononuclear phagocyte system extravascular hemolysis In addition we have been pursuing a strategy designed to circumvent the dosing challenges that have severely limited the field of complement therapeutics by developing an AP specific antibody that binds only the active product of the AP pathway protein Factor B Factor Bb fBb In this Phase I SBIR proposal we seek to continue the development of two monoclonal antibodies to fBb both of which inhibit AP mediated hemolysis in human and cynomolgus serum M is our lead antibody and shows complete specificity for the active fBb form with no binding to full length Factor B FB in solution M binds both fBb and FB with similar affinities and will be used to test the hypothesis that targeting only the active form of this protein will lead to improved PK PD In Specific Aim we will produce human chimeric forms of these antibodies hM and hM and confirm their activity and specificity in a series of in vitro assays In Specific Aim we will continue in vitro testing using experimental conditions relevant to PNH including both in PNH like RBCs and in RBCs from PNH patients provided by external collaborators In Specific Aim we will test hM and hM side by side in cynomolgus monkeys to compare their performance in PK PD studies Project Narrative True North is developing therapeutic antibodies to Factor B FB a key component of the alternative pathway AP of complement and part of the innate immune system Our targeted therapy will bind only the active form of FB fBb and will specifically inhibit activity further upstream in the pathway compared to the current anti C antibody eculizumab This is designed to be a more effective treatment for AP mediated diseases such as paroxysmal nocturnal hemoglobinuria by preventing accumulation of upstream split products