Validation of immunoassays used to assess immunogenicity to therapeutic monoclonal antibodies

Geng, Deqin; Shankar, Gopi; Schantz, Allen; Rajadhyaksha, Manoj; Davis, Hugh M.; Wagner, Carrie

doi:10.1016/j.jpba.2005.04.045

Cited by 64 publications

(32 citation statements)

References 5 publications

(6 reference statements)

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“…In its simplest form, a sandwich configuration of the therapeutic antibody used as capture (nontagged) and detection (tagged) reagents, respectively, should permit detection of both anti-isotypic and anti-idiotypic antibody responses (Fig. 2c) (47,48).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

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Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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“…Samples were considered positive when the OD values were above 1.625 times the mean value for the samples from naïve mice (background level), as suggested by Mire-Sluis (18). However, the value should not be less than 0.2 OD units since the precision deteriorates at absorbance levels below that value (8).…”

Section: Methodsmentioning

confidence: 99%

Influence of Antidrug Antibodies on Plectasin Efficacy and Pharmacokinetics

Brinch

Frimodt‐Møller

Høiby

et al. 2009

Antimicrob Agents Chemother

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Plectasin is a 4.4-kDa antimicrobial peptide with the potential to be a treatment of infections caused by gram-positive bacteria. Since plectasin is a large molecule compared to conventional antibiotics, the development of antidrug antibodies (ADAs) could be anticipated. The immunogenic properties of plectasin were assessed through immunization studies. In mice treated for 5 days with one to two daily subcutaneous doses of plectasin, no antibody response was observed. If the animals were immunized again, after a rest period, low levels of antibodies developed in approximately half the animals. Additionally, mice were immunized with plectasin in Freund's incomplete adjuvant (FIA). Ninety-two percent of these mice developed ADAs after repeated immunizations, with two-thirds having high levels of antibodies. An agar diffusion bioassay showed that sera from animals immunized with plectasin did not inhibit the efficacy of the drug, while hyperimmune sera from animals in which an immune response was provoked by immunization with plectasin in FIA reduced the efficacy of plectasin at the lowest concentration tested. Studies in the murine peritonitis model showed an excellent efficacy of plectasin for the treatment of Streptococcus pneumoniae infections both in naïve animals and in animals with ADAs. No difference in bacterial counts was seen when the animals were treated with plectasin at 2.5 mg/kg of body weight, a dose below the expected therapeutic level. When animals were treated with plectasin at 0.625 mg/kg, the effect was reduced but not neutralized in animals with high levels of ADAs. No animals showed signs of hypersensitivity or injection site reactions toward plectasin, and the half-life of the compound did not vary between animals with and without antibodies.

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“…The assay may also be beneficial for detection of low affinity ADAs, because it does not require stable binding of two drug molecules. However, the bridging assay is able to detect ADA of various Ig-subtypes, including IgM, and is applicable to all kinds of therapeutic antibodies [6,9], while the hsFcγRI-PG assay does not recognize Ig-subtypes other than IgG1 and therefore cannot detect less mature, potentially transient, immune responses of the IgM-type. The hsFcγRI-PG assay is also limited to therapeutic antibodies bearing the PG modification within the Fc domain.…”

Section: Overall Assay Comparisonmentioning

confidence: 99%

“…The assay allows for high-throughput testing with high sensitivity and easy implementation [4]. However, the bridging assay can be interfered by the presence of oligomeric soluble target, which can serve as a 'bridge' thus reducing specificity by providing a false-positive result [5][6][7][8], or residual drug, which can form an immune complex with antidrug antibodies (ADAs), thereby reducing sensitivity by providing a false-negative result [6,9,10]. Thus, there is a need for alternative assay formats that can overcome these potential weaknesses of the bridging design [11].…”

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confidence: 99%

Novel Drug and Soluble Target Tolerant Antidrug Antibody Assay for Therapeutic Antibodies Bearing The P329G Mutation

et al. 2017

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Aim:Bridging immunoassays for detection of antidrug antibodies (ADAs) are typically susceptible to high concentrations of residual drug. Sensitive drug-tolerant assays are, therefore, needed. Materials & methods: An immune complex assay to detect ADAs against therapeutic antibodies bearing Pro329Gly mutation was established. The assay uses antibodies specific for the Pro329Gly mutation for capture and human soluble Fcγ receptor for detection. Results: When compared with a bridging assay, the new assay showed similar precision, high sensitivity to IgG1 ADA and dramatically improved drug tolerance. However, it was not able to detect early (IgM-based) immune responses. Conclusion: Applied in combination with a bridging assay, the novel assay serves as orthogonal assay for immunogenicity assessment and allows further characterization of ADA responses.

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Validation of immunoassays used to assess immunogenicity to therapeutic monoclonal antibodies

Cited by 64 publications

References 5 publications

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Influence of Antidrug Antibodies on Plectasin Efficacy and Pharmacokinetics

Novel Drug and Soluble Target Tolerant Antidrug Antibody Assay for Therapeutic Antibodies Bearing The P329G Mutation

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