Clinical immunogenicity of the d -amino acid peptide therapeutic etelcalcetide: Method development challenges and anti-drug antibody clinical impact assessments
| Autor: | Raju Subramanian, Hongjie Deng, Michael Serenko, M. Benjamin Hock, Dohan Weeraratne, Benjamin M. Wu, Bethlyn Sloey, Mark A. Kroenke |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Drug Agonist medicine.drug_class media_common.quotation_subject Immunology Pharmacology 030226 pharmacology & pharmacy Antibodies 03 medical and health sciences 0302 clinical medicine Animals Humans Immunology and Allergy Medicine media_common Immunoassay Etelcalcetide biology medicine.diagnostic_test business.industry Immunogenicity Surface Plasmon Resonance 030104 developmental biology Immunization biology.protein Rabbits Antibody Peptides business Hapten |
| Zdroj: | Journal of Immunological Methods. 445:37-44 |
| ISSN: | 0022-1759 |
| DOI: | 10.1016/j.jim.2017.03.005 |
| Popis: | The immunogenicity risk assessment and bioanalytical strategy for novel therapeutics should account for both unique biophysical properties and potential consequences of immunogenicity. When assessing the immunogenicity risk of etelcalcetide, a peptide agonist of the calcium-sensing receptor, we considered the potential that the d-amino acid 'backbone' and biotransformation of etelcalcetide could allow the drug to act as a hapten. As a consequence, we validated and implemented a surface plasmon resonance immunoassay platform with both etelcalcetide and etelcalcetide-'carrier' surfaces to detect anti-drug antibodies (ADA). No evidence of in-vitro neutralizing activity with surrogate controls was detected despite multiple immunization approaches and a sensitive cell-based activity assay. Therefore, a neutralizing assay was not implemented for clinical support. We conducted an integrated analysis of immunogenicity data pooled from two pivotal placebo-controlled trials to define the clinical impact of anti-etelcalcetide antibodies. While both pre-existing and developing anti-etelcalcetide antibodies were detected, we show here that they have no consequences for clinical exposure, efficacy, or safety of etelcalcetide. |
| Databáze: | OpenAIRE |
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