Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents
Therapeutic monoclonal antibodies have exerted a transformative impact on clinical practice in last two decades. However, development of a therapeutic antibody remains a complex process. Various physiochemical and functional liabilities can compromise the production or the therapeutic efficacy of an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Antibodies |
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| Online Access: | https://www.mdpi.com/2073-4468/11/1/11 |
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| author | Maxime Lecerf Robin Lacombe Alexia Kanyavuz Jordan D. Dimitrov |
| author_facet | Maxime Lecerf Robin Lacombe Alexia Kanyavuz Jordan D. Dimitrov |
| author_sort | Maxime Lecerf |
| collection | DOAJ |
| description | Therapeutic monoclonal antibodies have exerted a transformative impact on clinical practice in last two decades. However, development of a therapeutic antibody remains a complex process. Various physiochemical and functional liabilities can compromise the production or the therapeutic efficacy of antibodies. One of these liabilities is the susceptibility to oxidation. In the present study, we portrayed an oxidation-dependent vulnerability of immunoglobulins that can be of concern for therapeutic antibodies. By using a library of 119 monoclonal IgG1 molecules, containing variable domain matching clinical-stage antibodies, we demonstrated that a substantial number of these molecules acquired antigen-binding polyreactivity upon exposure to ferrous ions. Statistical analyses revealed that the potential for induction of polyreactivity by the redox-active metal ions correlated with a higher number of somatic mutations in V genes encoding variable domains of heavy and light immunoglobulin chains. Moreover, the sensitive antibodies used with biased frequencies particular V gene families encoding variable domains of their light chains. Besides the exposure to ferrous ions the induction of polyreactivity of therapeutic antibodies occurred after contact with an unrelated pro-oxidative substance—hypochlorite ions. Our data also revealed that induction of polyreactivity by pro-oxidative agents did not impact the binding of antibodies to their cognate antigens. The results from this study may contribute for better selection of antibody therapeutics with suitable developability profiles. |
| first_indexed | 2024-03-09T20:11:35Z |
| format | Article |
| id | doaj.art-5046e22891c44e54a19b5803652220fc |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-03-09T20:11:35Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-5046e22891c44e54a19b5803652220fc2023-11-24T00:12:28ZengMDPI AGAntibodies2073-44682022-02-011111110.3390/antib11010011Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative AgentsMaxime Lecerf0Robin Lacombe1Alexia Kanyavuz2Jordan D. Dimitrov3Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006 Paris, FranceCentre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006 Paris, FranceTherapeutic monoclonal antibodies have exerted a transformative impact on clinical practice in last two decades. However, development of a therapeutic antibody remains a complex process. Various physiochemical and functional liabilities can compromise the production or the therapeutic efficacy of antibodies. One of these liabilities is the susceptibility to oxidation. In the present study, we portrayed an oxidation-dependent vulnerability of immunoglobulins that can be of concern for therapeutic antibodies. By using a library of 119 monoclonal IgG1 molecules, containing variable domain matching clinical-stage antibodies, we demonstrated that a substantial number of these molecules acquired antigen-binding polyreactivity upon exposure to ferrous ions. Statistical analyses revealed that the potential for induction of polyreactivity by the redox-active metal ions correlated with a higher number of somatic mutations in V genes encoding variable domains of heavy and light immunoglobulin chains. Moreover, the sensitive antibodies used with biased frequencies particular V gene families encoding variable domains of their light chains. Besides the exposure to ferrous ions the induction of polyreactivity of therapeutic antibodies occurred after contact with an unrelated pro-oxidative substance—hypochlorite ions. Our data also revealed that induction of polyreactivity by pro-oxidative agents did not impact the binding of antibodies to their cognate antigens. The results from this study may contribute for better selection of antibody therapeutics with suitable developability profiles.https://www.mdpi.com/2073-4468/11/1/11therapeutic antibodiesantibody developabilityoxidationantibody polyreactivityferrous ionshypochlorite |
| spellingShingle | Maxime Lecerf Robin Lacombe Alexia Kanyavuz Jordan D. Dimitrov Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents Antibodies therapeutic antibodies antibody developability oxidation antibody polyreactivity ferrous ions hypochlorite |
| title | Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents |
| title_full | Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents |
| title_fullStr | Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents |
| title_full_unstemmed | Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents |
| title_short | Functional Changes of Therapeutic Antibodies upon Exposure to Pro-Oxidative Agents |
| title_sort | functional changes of therapeutic antibodies upon exposure to pro oxidative agents |
| topic | therapeutic antibodies antibody developability oxidation antibody polyreactivity ferrous ions hypochlorite |
| url | https://www.mdpi.com/2073-4468/11/1/11 |
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