Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity
The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/7/1724 |
| _version_ | 1797407332671422464 |
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| author | Patricia E. Zerra Ernest T. Parker Wallace Hunter Baldwin John F. Healey Seema R. Patel James W. McCoy Courtney Cox Sean R. Stowell Shannon L. Meeks |
| author_facet | Patricia E. Zerra Ernest T. Parker Wallace Hunter Baldwin John F. Healey Seema R. Patel James W. McCoy Courtney Cox Sean R. Stowell Shannon L. Meeks |
| author_sort | Patricia E. Zerra |
| collection | DOAJ |
| description | The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323–339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA<sub>323–339</sub> in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA<sub>323–339</sub> does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies. |
| first_indexed | 2024-03-09T03:39:49Z |
| format | Article |
| id | doaj.art-ce4692653e9c4e57872dea79388e30ad |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T03:39:49Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-ce4692653e9c4e57872dea79388e30ad2023-12-03T14:42:46ZengMDPI AGBiomedicines2227-90592022-07-01107172410.3390/biomedicines10071724Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug ImmunityPatricia E. Zerra0Ernest T. Parker1Wallace Hunter Baldwin2John F. Healey3Seema R. Patel4James W. McCoy5Courtney Cox6Sean R. Stowell7Shannon L. Meeks8Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University, Atlanta, GA 30322, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USACenter for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University, Atlanta, GA 30322, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAJoint Program in Transfusion Medicine, Department of Pathology, Harvard Medical School, Boston, MA 02115, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USAThe development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323–339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA<sub>323–339</sub> in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA<sub>323–339</sub> does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies.https://www.mdpi.com/2227-9059/10/7/1724anti-drug antibodieshemophilia Afactor VIII inhibitorshumoral immunity |
| spellingShingle | Patricia E. Zerra Ernest T. Parker Wallace Hunter Baldwin John F. Healey Seema R. Patel James W. McCoy Courtney Cox Sean R. Stowell Shannon L. Meeks Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity Biomedicines anti-drug antibodies hemophilia A factor VIII inhibitors humoral immunity |
| title | Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity |
| title_full | Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity |
| title_fullStr | Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity |
| title_full_unstemmed | Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity |
| title_short | Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity |
| title_sort | engineering a therapeutic protein to enhance the study of anti drug immunity |
| topic | anti-drug antibodies hemophilia A factor VIII inhibitors humoral immunity |
| url | https://www.mdpi.com/2227-9059/10/7/1724 |
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