Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII

Pezeshkpoor, Behnaz; Sereda, Nadja; Berkemeier, Ann-Cristin; Matuschek, Isabell; Schwarz, Robert; Turecek, Peter. L.; Horneff, S.; Klein, Claudia; Goldmann, G.; Marquardt, Natascha; Albert, T.; Müller, Jens; Oldenburg, J.

doi:10.1016/j.jtha.2023.03.011

Cited by 4 publications

(11 citation statements)

References 55 publications

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“…One of the patients developed antibodies against both the FVIII and the PEG moiety, and the other patient developed antibodies only against the PEG moiety. 32 No FVIII inhibitors were detected; however, anti-PEG antibodies isolated from these 2 patients inhibited the activity of the 40PEG-BDD FVIII both in vivo and in vitro. Interestingly, the anti-PEG antibodies found in these 2 patients also bound to other PEGylated therapeutics such as 20PEG-FL FVIII rurioctocog alfa pegol, 40PEG-BDD FVIII turoctocog alfa pegol (N8-GP; Novo Nordisk), 60PEG-BDD FVIII damoctocog alfa pegol (BAY 94–9027; Bayer), and 40PEG FIX nonacog beta pegol (N9-GP; Novo Nordisk).…”

Section: Discussionmentioning

confidence: 91%

“…Recently, several papers indicated that antibodies binding to PEG could potentially affect the in vivo IR of PEGylated FVIII given to patients 42 , 43 , 44 and could even induce inhibitory activities resulting in the neutralization of PEGylated FVIII in vitro and in vivo. 32 Pezeshkpoor et al 32 presented data indicating that antibodies against the PEG moiety of a 40PEG-BDD FVIII drug (B-domain–deleted FVIII PEGylated with a 40-kDa PEG) abolished the efficacy of the drug. The authors characterized antibodies binding to PEG, which were observed in 2 of 46 patients with mild hemophilia A who were treated with the 40PEG-BDD FVIII drug.…”

Section: Discussionmentioning

confidence: 99%

“… 29 , 30 , 31 A 20-kDa branched PEG is conjugated to primary amine residues consisting of 2 10-kDa arms per attachment site. 25 , 32 , 33 Most of the amine residues are located at the surface of the FVIII molecule, mainly within the B-domain. 25 Compared with octocog alfa, the mean half-life of rurioctocog alfa pegol is 1.3- to 1.5-fold longer in children aged <12 years with severe hemophilia A, and 1.4- to 1.5-fold longer in patients aged ≥12 years with severe hemophilia A.…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity profile of rurioctocog alfa pegol in previously treated patients with severe congenital hemophilia A

Horling,

Reipert,

Allacher

et al. 2024

Blood Advances

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Rurioctocog alfa pegol is an extended half-life full-length recombinant factor VIII (FVIII) bound to 20 kDa polyethylene glycol (PEG) that has been shown to be well tolerated and efficacious in the treatment and prevention of bleeding events in previously treated patients with severe hemophilia A. Here, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol including a total of 360 unique previously treated patients with severe hemophilia A. The analysis included treatment-emerging FVIII neutralizing antibodies (FVIII inhibitors), pre-existing and treatment-emerging antibodies binding to FVIII, PEG-FVIII, or PEG, and treatment-emerging antibodies binding to Chinese hamster ovary host cell proteins. Moreover, the potential association between the presence of these binding antibodies and adverse events (AEs) observed in patients was investigated and the potential impact of these antibodies on the incremental recovery of rurioctocog alfa pegol in patients was analyzed. Overall, the data indicate that rurioctocog alfa pegol is not associated with any unexpected immunogenicity characteristics. One of the 360 patients developed a transient FVIII inhibitor with a titer of 0.6 BU/mL, which was not associated with any serious AEs. Antibodies binding to FVIII, PEG-FVIII, or PEG were not detected at the time when the inhibitor was present. Moreover, 54 of the 360 patients either entered the clinical studies with pre-existing binding antibodies or developed these antibodies after exposure to rurioctocog alfa pegol. These antibodies were transient in most patients and did not show any causal relationship to either AEs or spontaneous bleeding episodes.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunogenicity profile of rurioctocog alfa pegol in previously treated patients with severe congenital hemophilia A

Horling,

Reipert,

Allacher

et al. 2024

Blood Advances

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“…Thus, sensitive as well as specific immunological assays for detection of total FVIII-bAb are valuable tools for further assessment of threshold NBA results. [10][11][12] Furthermore, the presence of non-inhibitory FVIII-bAb may result in an enhanced clearance of administered FVIII concentrates, giving point to detection of FVIII-bAb in inhibitor-negative patients that show reduced half-life and/or recovery of administered FVIII. 13 Finally, especially in the context of biopharmaceutical immunogenicity, detection of FVIII-bAb may be an early sign of inhibitor formation.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, cases of borderline plasma inhibitory activity (around 0.6 BU) in absence of detectable FVIII‐bAb are still observed. Thus, sensitive as well as specific immunological assays for detection of total FVIII‐bAb are valuable tools for further assessment of threshold NBA results 10–12 . Furthermore, the presence of non‐inhibitory FVIII‐bAb may result in an enhanced clearance of administered FVIII concentrates, giving point to detection of FVIII‐bAb in inhibitor‐negative patients that show reduced half‐life and/or recovery of administered FVIII 13 .…”

Section: Introductionmentioning

confidence: 99%

Two‐center validation of assays for the detection of binding and neutralizing anti‐factor VIII antibodies

Müller,

Neimanis,

Kahle

et al. 2023

Haemophilia

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IntroductionPatients with hemophilia A treated with coagulation Factor VIII (FVIII) products are at risk for developing anti‐FVIII antibodies. The ABIRISK Consortium aimed to provide knowledge on the formation and detection of anti‐drug antibodies against biopharmaceutical products, including FVIII. Accordingly, standardized and validated assays for the detection of binding (total) and neutralizing antibodies are needed.AimTwo‐center validation of an ELISA for the detection of total FVIII‐binding IgG‐antibodies and Nijmegen‐Bethesda assays for the quantification of FVIII‐neutralizing antibodies according to consensus validation guidelines.MethodsValidation of assays at both sites was done according to published recommendations and included preanalytics, the determination of key assay parameters, including cut‐points, assay sensitivity, precision, and FVIII interference.ResultsThe validated assays reproducibly detected FVIII‐binding and ‐neutralizing antibodies with comparable performance in both laboratories. Floating screening cut‐points were established for both assays. Determined mass‐based sensitivity of both assays (all values ≤66 ng/mL) complied with the minimum sensitivity for the detection of anti‐drug antibodies as recommended by the FDA (<100 ng/mL). Intra‐ and inter‐assay coefficients of variation did not exceed 25%. Assay validation further revealed that pre‐analytical heat treatment led to potentially false‐positive ELISA results, while up to 0.15 IU/mL, residual FVIII showed no significant impact. Overall, good agreement of results was found for patient samples analyzed at both study sites.ConclusionComprehensive validation of different anti‐FVIII‐antibody assays in two laboratories gave novel insights into the impact of pre‐analytical sample treatment as well as the comparability of test results generated by the use of methodically different assays.

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Comprehensive domain-specific analysis and immunoglobulin G profiling of anti–factor VIII antibodies using a bead-based multiplex immunoassay

Pezeshkpoor,

Berkemeier,

Herbst

et al. 2024

Journal of Thrombosis and Haemostasis

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Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII

Cited by 4 publications

References 55 publications

Immunogenicity profile of rurioctocog alfa pegol in previously treated patients with severe congenital hemophilia A

Immunogenicity profile of rurioctocog alfa pegol in previously treated patients with severe congenital hemophilia A

Two‐center validation of assays for the detection of binding and neutralizing anti‐factor VIII antibodies

Comprehensive domain-specific analysis and immunoglobulin G profiling of anti–factor VIII antibodies using a bead-based multiplex immunoassay

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