CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering
| Autor: | Margaret A. Lindorfer, Martine E.D. Chamuleau, Richard Burack, Paul W. H. I. Parren, Clive S. Zent, Ronald P. Taylor, Karl R. VanDerMeid, Tuna Mutis, Rob N. de Jong, Jillian C. Tupitza, Hilma J. van der Horst, Janine Schuurman, Erika M. Cook, Kristin Strumane, Frank J. Beurskens, Esther C.W. Breij, Simone C. Oostindie |
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| Přispěvatelé: | Hematology laboratory, CCA - Cancer biology and immunology, Hematology, Molecular cell biology and Immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
CD20
biology medicine.drug_class Chemistry Hematology Complement System Proteins Monoclonal antibody Antigens CD20 Article Antibodies 03 medical and health sciences 0302 clinical medicine Antigen Cell culture Cell Therapy & Immunotherapy Cancer cell Monoclonal Cancer research medicine biology.protein Cluster Analysis Antibody Cytotoxicity 030215 immunology |
| Zdroj: | Haematologica Haematologica, 104(9), 1841-1852. Ferrata Storti Foundation Haematologica, 104(9), 1841-1852. FERRATA STORTI FOUNDATION Oostindie, S C, Van Der Horst, H J, Lindorfer, M A, Cook, E M, Tupitza, J C, Zent, C S, Burack, R, VanDerMeid, K R, Strumane, K, Chamuleau, M E D, Mutis, T, De Jong, R N, Schuurman, J, Breij, E C W, Beurskens, F J, Parren, P W H I & Taylor, R P 2019, ' CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering ', Haematologica, vol. 104, no. 9, pp. 1841-1852 . https://doi.org/10.3324/haematol.2018.207266 |
| ISSN: | 0390-6078 |
| Popis: | CD20 monoclonal antibody therapies have significantly improved the outlook for patients with B-cell malignancies. However, many patients acquire resistance, demonstrating the need for new and improved drugs. We previously demonstrated that the natural process of antibody hexamer formation on targeted cells allows for optimal induction of complement-dependent cytotoxicity. Complement-dependent cytotoxicity can be potentiated by introducing a single point mutation such as E430G in the IgG Fc domain that enhances intermolecular Fc-Fc interactions between cell-bound IgG molecules, thereby facilitating IgG hexamer formation. Antibodies specific for CD37, a target that is abundantly expressed on healthy and malignant B cells, are generally poor inducers of complement-dependent cytotoxicity. Here we demonstrate that introduction of the hexamerization-enhancing mutation E430G in CD37-specific antibodies facilitates highly potent complement-dependent cytotoxicity in chronic lymphocytic leukemia cells ex vivo. Strikingly, we observed that combinations of hexamerization-enhanced CD20 and CD37 antibodies cooperated in C1q binding and induced superior and synergistic complement-dependent cytotoxicity in patient-derived cancer cells compared to the single agents. Furthermore, CD20 and CD37 antibodies colocalized on the cell membrane, an effect that was potentiated by the hexamerization-enhancing mutation. Moreover, upon cell surface binding, CD20 and CD37 antibodies were shown to form mixed hexameric antibody complexes consisting of both antibodies each bound to their own cognate target, so-called hetero-hexamers. These findings provide novel insights into the mechanisms of synergy in antibody-mediated complement-dependent cytotoxicity and provide a rationale to explore Fc-engineering and antibody hetero-hexamerization as a tool to enhance the cooperativity and therapeutic efficacy of antibody combinations. |
| Databáze: | OpenAIRE |
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