Reformatting Rituximab into Human IgG2 and IgG4 Isotypes Dramatically Improves Apoptosis Induction In Vitro
| Autor: | Annette Sieron, Jennifer D. Könitzer, Barbara Enenkel, Angelika Wacker |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Programmed cell death
Recombinant Fusion Proteins Molecular Sequence Data lcsh:Medicine Apoptosis Protein Engineering Immunoglobulin G Cell Line Tumor hemic and lymphatic diseases medicine Humans Cytotoxic T cell Amino Acid Sequence lcsh:Science CD20 Multidisciplinary biology lcsh:R Antibody-Dependent Cell Cytotoxicity Molecular biology Protein Structure Tertiary Cell biology Cell culture biology.protein lcsh:Q Rituximab Antibody Research Article medicine.drug |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 12, p e0145633 (2015) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0145633 |
| Popis: | The direct induction of cell death, or apoptosis, in target cells is one of the effector mechanisms for the anti CD20 antibody Rituximab. Here we provide evidence that Rituximab's apoptotic ability is linked to the antibody IgG isotype. Reformatting Rituximab from the standard human IgG1 heavy chain into IgG2 or IgG4 boosted in vitro apoptosis induction in the Burkitt's lymphoma B cell line Ramos five and four-fold respectively. The determinants for this behavior are located in the hinge region and CH1 domain of the heavy chain. By transplanting individual IgG2 or IgG4 specific amino acid residues onto otherwise IgG1 like backbones, thereby creating hybrid antibodies, the same enhancement of apoptosis induction could be achieved. The cysteines at position 131 of the CH1 domain and 219 in the hinge region, involved in IgG2 and IgG4 disulfide formation, were found to be of particular structural importance. Our data indicates that the hybrid antibodies possess a different CD20 binding mode than standard Rituximab, which appears to be key in enhancing apoptotic ability. The presented work opens up an interesting engineering route for enhancing the direct cytotoxic ability of therapeutic antibodies. |
| Databáze: | OpenAIRE |
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