Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment
Anti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2016/2921758 |
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| _version_ | 1849399387527053312 |
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| author | Jane Ruppel Ann Brady Rebecca Elliott Cecilia Leddy Marco Palencia Daniel Coleman Jessica A. Couch Eric Wakshull |
| author_facet | Jane Ruppel Ann Brady Rebecca Elliott Cecilia Leddy Marco Palencia Daniel Coleman Jessica A. Couch Eric Wakshull |
| author_sort | Jane Ruppel |
| collection | DOAJ |
| description | Anti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab′)2, a potential antitumor therapeutic, were detected in cynomolgus monkey serum, which presented a challenge in developing assays for detecting treatment induced ATA. A total ATA assay was developed using a bridging ELISA that detected both anti-CDR and anti-framework ATA including anti-hinge reactivity. A competition assay that could detect 500 ng/mL of anti-CDR ATA in the presence of preexisting ATA was also developed to determine ATA specific to the anti-DLL4 F(ab′)2 CDR using anti-DLL4 F(ab′)2 and a control F(ab′)2. We used these assay methods in a cynomolgus monkey in vivo study to successfully evaluate total and anti-CDR ATA. The preexisting anti-hinge reactivity was also observed to a lesser extent in human serum, and a similar approach could be applied for specific immunogenicity assessment in clinical trials. |
| format | Article |
| id | doaj-art-a2c09b33e27145b9ac722fdb09316f8e |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-a2c09b33e27145b9ac722fdb09316f8e2025-08-20T03:38:19ZengWileyJournal of Immunology Research2314-88612314-71562016-01-01201610.1155/2016/29217582921758Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity AssessmentJane Ruppel0Ann Brady1Rebecca Elliott2Cecilia Leddy3Marco Palencia4Daniel Coleman5Jessica A. Couch6Eric Wakshull7BioAnalytical Sciences Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USABioAnalytical Sciences Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USABioAnalytical Sciences Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USABioAnalytical Sciences Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USABiosample and Repository Management Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USANonclinical Biostatistics Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USASafety Assessment Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USABioAnalytical Sciences Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USAAnti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab′)2, a potential antitumor therapeutic, were detected in cynomolgus monkey serum, which presented a challenge in developing assays for detecting treatment induced ATA. A total ATA assay was developed using a bridging ELISA that detected both anti-CDR and anti-framework ATA including anti-hinge reactivity. A competition assay that could detect 500 ng/mL of anti-CDR ATA in the presence of preexisting ATA was also developed to determine ATA specific to the anti-DLL4 F(ab′)2 CDR using anti-DLL4 F(ab′)2 and a control F(ab′)2. We used these assay methods in a cynomolgus monkey in vivo study to successfully evaluate total and anti-CDR ATA. The preexisting anti-hinge reactivity was also observed to a lesser extent in human serum, and a similar approach could be applied for specific immunogenicity assessment in clinical trials.http://dx.doi.org/10.1155/2016/2921758 |
| spellingShingle | Jane Ruppel Ann Brady Rebecca Elliott Cecilia Leddy Marco Palencia Daniel Coleman Jessica A. Couch Eric Wakshull Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment Journal of Immunology Research |
| title | Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment |
| title_full | Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment |
| title_fullStr | Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment |
| title_full_unstemmed | Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment |
| title_short | Preexisting Antibodies to an F(ab′)2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment |
| title_sort | preexisting antibodies to an f ab 2 antibody therapeutic and novel method for immunogenicity assessment |
| url | http://dx.doi.org/10.1155/2016/2921758 |
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