title: Clinical immunogenicity of the d-amino acid peptide therapeutic etelcalcetide: Method development challenges and anti-drug antibody clinical impact assessments.
abstract: 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.
authors.affiliation: Amgen Inc., Medical Sciences, Thousand Oaks, CA, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kroenke
authors.affiliation: Amgen Inc., Pharmacokinetics and Drug Metabolism, Thousand Oaks, CA, United States.
authors.forename: Dohan K
authors.initials: DK
authors.lastname: Weeraratne
authors.affiliation: Amgen Inc., Global Biostatistical Sciences, Thousand Oaks, CA, United States.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.affiliation: Amgen Inc., Medical Sciences, Thousand Oaks, CA, United States.
authors.forename: Bethlyn
authors.initials: B
authors.lastname: Sloey
authors.affiliation: Amgen Inc., Pharmacokinetics and Drug Metabolism, Thousand Oaks, CA, United States.
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Amgen Inc., Medical Sciences, Thousand Oaks, CA, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Amgen Inc., Global Safety, Cambridge, MA, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Serenko
authors.affiliation: Amgen Inc., Medical Sciences, Thousand Oaks, CA, United States. Electronic address: mhock@amgen.com.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Hock
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D006801:Humans; D007118:Immunoassay; D010455:Peptides / Q000276:immunology*; D011817:Rabbits; D020349:Surface Plasmon Resonance
chemical_list: D000906:Antibodies; D010455:Peptides; C583569:etelcalcetide hydrochloride
keywords: ADA impact assessment; Anti-drug antibody; Calcimimetic; Etelcalcetide; Immunogenicity; Surface plasmon resonance