A false sense of security? Can tiered approach be trusted to accurately classify immunogenicity samples?

Abstract

Detecting and characterizing of anti-drug antibodies (ADA) against a protein therapeutic are crucially important to monitor the unwanted immune response. Usually a multi-tiered approach that initially rapidly screens for positive samples that are subsequently confirmed in a separate assay is employed for testing of patient samples for ADA activity. In this manuscript we evaluate the ability of different methods used to classify subject with screening and competition based confirmatory assays. We find that for the overall performance of the multi-stage process the method used for confirmation is most important where a t-test is best when differences are moderate to large. Moreover we find that, when differences between positive and negative samples are not sufficiently large, using a competition based confirmation step does yield poor classification of positive samples.

Chronic Toxicology Studies of Basal Insulin Peglispro in Rats and Dogs: A Novel, PEGylated Insulin Lispro Analog with a Prolonged Duration of Action

“…The incidences of anti-BIL antibody titers were observed as follows: carcinogenicity animals: 2/47 rats (control), 6/55 rats (0.17-mg/kg BIL), 9/42 rats (0.45-mg/kg BIL), 8/53 rats (1.15-mg/kg BIL) and toxicokinetic animals: 0/6 rats (control), 1/5 rats (0.17-mg/kg BIL), 0/3 rats (0.45-mg/kg BIL), and 0/6 rats (1.15-mg/kg BIL). As can be expected for screening immunogenicity assays, there was a false-positive rate of about 4% (Jaki, Allacher, and Horling 2016). However, because measureable concentrations of BIL were found in all samples with anti-BIL antibodies and very high concentrations of BIL can interfere with the accuracy of the anti-BIL antibody assay, false-negative results potentially may have been reported.…”

Prediction intervals for all of M future observations based on linear random effects models

“…For validation, a bioassay might be carried out by several experimenters on different days using samples obtained from different individuals resulting in cross‐classified or hierarchical designs (Francq et al, 2020). For ADA cut point estimation, samples of several individuals may be processed by different experimenters on different plates on several days, resulting in designs that range from a simple one‐way layout to complex designs with some random factors crossed and some nested (Hoffman & Berger, 2011; Jaki et al, 2016; Shen & Dai, 2021; Zhang, Zhang, Kubiak, & Yang, 2013). Data about historical controls regarding rats and mice obtained from long‐time carcinogenicity studies are provided on the homepage of the National Toxicology Program (NTP, 2021).…”

“…Nevertheless, the literature lacks methods for the computation and application of PI to other models in that research area. Another field of application occurs in early phases of drug development such as the detection of anti‐drug antibodies (ADA) (Hoffman & Berger, 2011; Jaki, Allacher, & Horling, 2016). In such a bioassay, the antibody reaction is evaluated for a set of nonresponders as well as for patients with unclear status.…”

A Survey and Analysis on the Sense of Nuclear Safety & Security for the Public: A Chinese Perspective

“…Both domestic and foreign scholars have investigated the sense of public sense of nuclear safety & security [1][2][3][4][5][6][7][8][9][10][11]. Among them, scholars have studied the composition of the sense of informational users, which has two dimensions and six aspects, including the security technology, usability, and assurance, categorized into environmental factors and experience, preferences, and knowledge, categorized into personal factors.…”