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Enhancing CDC and ADCC of CD19 Antibodies by Combining Fc Protein-Engineering with Fc Glyco-Engineering
| Content Provider | MDPI |
|---|---|
| Author | Sophia, Roßkopf Ira, Alexandra Münnich Thies, Rösner Eichholz, Klara Marie Winterberg, Dorothee Diemer, Katarina Julia Lutz, Sebastian Klausz, Katja Valerius, Thomas Schewe, Denis Martin Humpe, Andreas Gramatzki, Martin Peipp, Matthias Kellner, Christian |
| Copyright Year | 2020 |
| Description | Background: Native cluster of differentiation (CD) 19 targeting antibodies are poorly effective in triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are crucial effector functions of therapeutic antibodies in cancer immunotherapy. Both functions can be enhanced by engineering the antibody’s Fc region by altering the amino acid sequence (Fc protein-engineering) or the Fc-linked glycan (Fc glyco-engineering). We hypothesized that combining Fc glyco-engineering with Fc protein-engineering will rescue ADCC and CDC in CD19 antibodies. Results: Four versions of a CD19 antibody based on tafasitamab’s V-regions were generated: a native IgG1, an Fc protein-engineered version with amino acid exchanges S267E/H268F/S324T/G236A/I332E (EFTAE modification) to enhance CDC, and afucosylated, Fc glyco-engineered versions of both to promote ADCC. Irrespective of fucosylation, antibodies carrying the EFTAE modification had enhanced C1q binding and were superior in inducing CDC. In contrast, afucosylated versions exerted an enhanced affinity to Fcγ receptor IIIA and had increased ADCC activity. Of note, the double-engineered antibody harboring the EFTAE modification and lacking fucose triggered both CDC and ADCC more efficiently. Conclusions: Fc glyco-engineering and protein-engineering could be combined to enhance ADCC and CDC in CD19 antibodies and may allow the generation of antibodies with higher therapeutic efficacy by promoting two key functions simultaneously. |
| Starting Page | 63 |
| e-ISSN | 20734468 |
| DOI | 10.3390/antib9040063 |
| Journal | Antibodies |
| Issue Number | 4 |
| Volume Number | 9 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2020-11-17 |
| Access Restriction | Open |
| Subject Keyword | Antibodies Oncology Antibody Therapy Cluster of Differentiation 19 (cd19) Cd19 Fc Fragment Crystallizable (fc) Fc Engineering Complement-dependent Cytotoxicity (cdc) Antibody-dependent Cell-mediated Cytotoxicity (adcc) |
| Content Type | Text |
| Resource Type | Article |
