A novel bispecific antibody platform to direct complement activity for efficient lysis of target cells
| Autor: | Christos A. Kyratsous, Ermelinda Damko, John C. Lin, Karoline A Meagher, Robert Babb, Haibo Qiu, Sook Yen E, Priya Aneja, Ashique Rafique, Courtney M. Williams, Macdonald Lynn, Hans Gartner, Andrew J. Murphy, Amanda D’ Orvilliers, Jonathan W. Cruz, Vera Voronina, Bhavika Modi, Alida Coppi, Gang Chen, Neil Stahl, Naxin Tu, George Ehrlich, Brinda Prasad, Brandy L. Bennett, Terra Potocky, William C. Olson |
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| Rok vydání: | 2019 |
| Předmět: |
Cytotoxicity
Immunologic 0301 basic medicine Staphylococcus aureus Science Transgene Cell Mice Transgenic Complement Membrane Attack Complex Plasma protein binding Biologics Article Mice 03 medical and health sciences 0302 clinical medicine Antigen In vivo Antibodies Bispecific medicine Animals Humans Cytotoxicity Complement Activation Multidisciplinary biology Antimicrobials Chemistry Antibody-Dependent Cell Cytotoxicity Complement System Proteins Staphylococcal Infections Cell biology Complement system Disease Models Animal 030104 developmental biology medicine.anatomical_structure biology.protein Medicine Antibody 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-16 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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