Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab
Inhibition of complement activation via the overexpression of complement-regulatory proteins (CRPs), most notably CD46, CD55 and CD59, is an efficient mechanism of disguise of cancer cells from a host immune system. This phenomenon extends to counteract the potency of therapeutic antibodies that cou...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/5208 |
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| author | Katharina Stadlbauer Peter Andorfer Gerhard Stadlmayr Florian Rüker Gordana Wozniak-Knopp |
| author_facet | Katharina Stadlbauer Peter Andorfer Gerhard Stadlmayr Florian Rüker Gordana Wozniak-Knopp |
| author_sort | Katharina Stadlbauer |
| collection | DOAJ |
| description | Inhibition of complement activation via the overexpression of complement-regulatory proteins (CRPs), most notably CD46, CD55 and CD59, is an efficient mechanism of disguise of cancer cells from a host immune system. This phenomenon extends to counteract the potency of therapeutic antibodies that could lyse target cells by eliciting complement cascade. The manifold functions and ubiquitous expression of CRPs preclude their systemic specific inhibition. We selected CD59-specific Fc fragments with a novel antigen binding site (Fcabs) from yeast display libraries using recombinant antigens expressed in bacterial or mammalian cells. To produce a bispecific antibody, we endowed rituximab, a clinically applied anti-CD20 antibody, used for therapy of various lymphoid malignancies, with an anti-CD59 Fcab. This bispecific antibody was able to induce more potent complement-dependent cytotoxicity for CD20 and CD59 expressing Raji cell line measured with lactate dehydrogenase-release assay, but had no effect on the cells with lower levels of the primary CD20 antigen or CD20-negative cells. Such molecules are promising candidates for future therapeutic development as they elicit a higher specific cytotoxicity at a lower concentration and hence cause a lower exhaustion of complement components. |
| first_indexed | 2024-03-10T04:03:03Z |
| format | Article |
| id | doaj.art-1a3f0a9a09d44abb8dec2c63f7204481 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:03:03Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1a3f0a9a09d44abb8dec2c63f72044812023-11-23T08:28:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239520810.3390/ijms23095208Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by RituximabKatharina Stadlbauer0Peter Andorfer1Gerhard Stadlmayr2Florian Rüker3Gordana Wozniak-Knopp4Christian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna, AustriaChristian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna, AustriaChristian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna, AustriaChristian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna, AustriaChristian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna, AustriaInhibition of complement activation via the overexpression of complement-regulatory proteins (CRPs), most notably CD46, CD55 and CD59, is an efficient mechanism of disguise of cancer cells from a host immune system. This phenomenon extends to counteract the potency of therapeutic antibodies that could lyse target cells by eliciting complement cascade. The manifold functions and ubiquitous expression of CRPs preclude their systemic specific inhibition. We selected CD59-specific Fc fragments with a novel antigen binding site (Fcabs) from yeast display libraries using recombinant antigens expressed in bacterial or mammalian cells. To produce a bispecific antibody, we endowed rituximab, a clinically applied anti-CD20 antibody, used for therapy of various lymphoid malignancies, with an anti-CD59 Fcab. This bispecific antibody was able to induce more potent complement-dependent cytotoxicity for CD20 and CD59 expressing Raji cell line measured with lactate dehydrogenase-release assay, but had no effect on the cells with lower levels of the primary CD20 antigen or CD20-negative cells. Such molecules are promising candidates for future therapeutic development as they elicit a higher specific cytotoxicity at a lower concentration and hence cause a lower exhaustion of complement components.https://www.mdpi.com/1422-0067/23/9/5208bispecific antibodyCD20CD59complement-dependent cytotoxicitycomplement regulatory proteinFcab |
| spellingShingle | Katharina Stadlbauer Peter Andorfer Gerhard Stadlmayr Florian Rüker Gordana Wozniak-Knopp Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab International Journal of Molecular Sciences bispecific antibody CD20 CD59 complement-dependent cytotoxicity complement regulatory protein Fcab |
| title | Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab |
| title_full | Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab |
| title_fullStr | Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab |
| title_full_unstemmed | Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab |
| title_short | Bispecific mAb<sup>2</sup> Antibodies Targeting CD59 Enhance the Complement-Dependent Cytotoxicity Mediated by Rituximab |
| title_sort | bispecific mab sup 2 sup antibodies targeting cd59 enhance the complement dependent cytotoxicity mediated by rituximab |
| topic | bispecific antibody CD20 CD59 complement-dependent cytotoxicity complement regulatory protein Fcab |
| url | https://www.mdpi.com/1422-0067/23/9/5208 |
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