Clinical immunogenicity of the d-amino acid peptide therapeutic etelcalcetide: Method development challenges and anti-drug antibody clinical impact assessments

Abstract The immunogenicityrisk assessment and bioanalytical strategy for novel therapeutics should account for both unique biophysical properties and potential consequences of immunogenicity. When assessing the immunogenicityrisk of etelcalcetide, a peptide agonist of the calcium-sensing receptor, we considered the potential that the d- amino acid‘backbone’ and biotransformation of etelcalcetidecould allow the drug to act as a hapten. As a consequence, we validated and implemented a surface plasmon resonance immunoassay platform with both etelcalcetideand 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 immunogenicitydata pooled from two pivotal placebo-controlled trials to define the clinical impact of anti- etelcalcetideantibodies. While both pre-existing and developing anti- etelcalcetideantibodies were detected, we show here that they have no consequences for clinical exposure, efficacy, or safety of etelcalcetide.