Immunogenicity Testing Strategy and Bioanalytical Assays for Antibody–Drug Conjugates

Abstract

Immunogenicity assays incorporating epitope determination may provide additional information about the characteristics of induced antitherapeutic antibodies, including the magnitude and timing of the various types of antibody responses.

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

“…These results (among others (20)) for trastuzumab confirm that the particular linker and small-molecule drug may contribute unique immunogenicity properties. Hoofring et al also demonstrate that ADA in a rat preclinical study can impact PK (43). This study also used a direct detection domain specificity approach to show that most individual animals developed immunoreactivity to both the mAb and the linker/small-molecule drug component of the ADC.…”

“…In contrast, an advantage of the detection approach is its sensitivity for minor components of a polyclonal antibody response. Hoofring et al demonstrate that with surrogate controls, detection of a minor anti-linker/toxin or anti-mAb ADA (in the presence of 300-fold or greater molar excess of ADA with specificity for the alternative domain) was only possible with a direct detection strategy (43). Whether antibodies that represent a minor variant of the anti-ADC response are of clinical significance remains undetermined.…”

Assessment of clinical immunogenicity of inotuzumab ozogamicin in patients with non-Hodgkin lymphoma and acute lymphoblastic leukemia

“…Evaluating immunogenicity is a critical component of the clinical development of large-molecule biotherapeutics. The development of ADAs may have profound consequences on the PK of a drug, as well as its safety and/ or efficacy (Hoofring et al, 2013;Sauerborn & van Dongen, 2014). In this bioanalytical analysis for InO, a bridging ECL and a cell-based assay were used to detect ADAs and neutralizing antibodies, respectively, in patients with ALL.…”

“…Samples for immunogenicity assessments were collected based on time points specified in each individual clinical study. During early NHL studies, immunogenicity response was measured using an ELISA platform, which was considered a standard of practice at the time, for the detection of Hoofring et al, 2013;Jani et al, 2015;Shankar et al, 2008). Similar bridging assay platforms have successfully been used for other approved ADCs (CarrascoTriguero et al, 2013).…”

“…Independent anti-InO and anti-rituximab ELISA methods were developed and validated as per the scientific experience and best practices of laboratories where assays were developed. In the recent ALL studies, a Meso Scale Discovery (MSD) based bridging electrochemiluminescence (ECL) assay was developed and validated as per the regulatory expectations and current industry white papers (Center for Drug Evaluation and Research, US Food and Drug Administration, 2009; Committee for Medicinal Products for Human Use, 2007;Hoofring et al, 2013;Jani et al, 2015;Shankar et al, 2008). Similar bridging assay platforms have successfully been used for other approved ADCs (Carrasco-Triguero et al, 2013).…”