A Recombinant Bispecific CD20×CD95 Antibody With Superior Activity Against Normal and Malignant B-cells

• Published in: Molecular therapy 2016-02, Vol.24 (2), p.298-305
• Main Authors: Nalivaiko, Kristina, Hofmann, Martin, Kober, Karina, Teichweyde, Nadine, Krammer, Peter H, Rammensee, Hans-Georg, Grosse-Hovest, Ludger, Jung, Gundram
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antibodies; Antibodies, Bispecific - administration & dosage; Antibodies, Bispecific - pharmacology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antigens; Antigens, CD20 - immunology; Apoptosis; Autoimmune diseases; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cancer research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells; Cytotoxicity; fas Receptor - immunology; Genetic engineering; Humans; Immunology; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Lymphocyte Activation - drug effects; Lymphoma; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - immunology; Medical research; Melanoma; Mice; Original; Reagents
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2015.209

Monoclonal antibodies directed to the B-cell-specific CD20-antigen are successfully used for the treatment of lymphomas and autoimmune diseases. Here, we compare the anti-B-cell activity of three different antibodies directed to CD20: (i) a chimeric, monospecific antibody, (ii) an Fc-optimized variant thereof, and (iii) a bispecific CD20×CD95-antibody in a newly developed recombinant format, termed Fabsc. The bispecific antibody specifically triggers the CD95 death receptor on malignant, as well as activated, normal B-cells. We found that the capability of this antibody to suppress the growth of malignant B-cells in vitro and in vivo and to specifically deplete normal, activated B-cells from peripheral blood mononuclear cell (PBMC) cultures was superior to that of the Fc-optimized monospecific antibody. This antibody in turn was more effective than its nonoptimized variant. Moreover, the bispecific antibody was the only reagent capable of significantly suppressing antibody production in vitro. Our findings imply that the bispecific CD20×CD95-antibody might become a new, prototypical reagent for the treatment of B-cell-mediated autoimmune disease.