A novel bispecific antibody platform to direct complement activity for efficient lysis of target cells

• Main Authors: Jonathan W. Cruz, Ermelinda Damko, Bhavika Modi, Naxin Tu, Karoline Meagher, Vera Voronina, Hans Gartner, George Ehrlich, Ashique Rafique, Robert Babb, Priya Aneja, Terra B. Potocky, Amanda D’ Orvilliers, Alida Coppi, Sook Yen E, Haibo Qiu, Courtney M. Williams, Brandy L. Bennett, Gang Chen, Lynn Macdonald, William Olson, John C. Lin, Neil Stahl, Andrew J. Murphy, Christos A. Kyratsous, Brinda C. Prasad
• Format: Article
• Language: English
• Published: Nature Publishing Group 2019-08-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-019-48461-1

Abstract Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.