Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma

Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice, Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice

Abstract

Introduction: Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma.

Objective: The objectives of this study were to characterize the potential immunogenic properties of tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials.

Methods: The oligosaccharide structure of tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699).

Results: No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1-every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2-Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1-Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2-Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no tralokinumab-related severe hypersensitivity or anaphylaxis reactions.

Conclusion: Preclinical assessments suggested a low likelihood of immunogenicity for tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with tralokinumab treatment. Together, the results suggest that tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

Conflict of interest statement

Conflicts of interest

Yuling Li was an employee of MedImmune, the biologics division of AstraZeneca, at the time the study took place; her current affiliation is CBT Pharmaceuticals. Jihong Wang and Weichen Xu are employees of MedImmune, the biologics division of AstraZeneca. Nicholas White is an employee of MedImmune and an AstraZeneca shareholder. Mats Carlsson, Martin Braddock, and Ayman Megally are employees of AstraZeneca, the sponsor of STRATOS 1 and STRATOS 2. Gene Colice is an employee of and holds stock options in AstraZeneca. Gillian Hunter is a consultant employed by AstraZeneca.

Ethical approval and informed consent

STRATOS 1 and STRATOS 2 were performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements, and the AstraZeneca policy on Bioethics. All participating centers obtained approval from an independent ethics committee and all participants provided written informed consent.

Figures

Fig. 1
Fig. 1
Oligosaccharide profile of tralokinumab. Separation of 2-aminobenzamide labeled glycans from tralokinumab by hydrophilic interaction liquid chromatography. f fucose, G galactose, GN N-acetyl-glucosamine, M mannose, NGc N-glycolylneuraminic acid
Fig. 2
Fig. 2
Structure and nomenclature of oligosaccharides in the tralokinumab Fab region. f fucose, G galactose, GlcNAc N-acetylglucosamine, Man mannose, NGc N-glycolylneuraminic acid
Fig. 3
Fig. 3
Characterization of tralokinumab with different degrees of reduction by non-reducing gel electrophoresis: (a) non-reduced; (b) reduced; and (c) partially reduced. HHL two heavy chains + one light chain, IgG immunoglobulin G
Fig. 4
Fig. 4
Ion exchange chromatography profiles of tralokinumab and mavrilimumab Fab-arm exchange under (a) physiological conditions and (b) non-physiological conditions
Fig. 5
Fig. 5
Patient flow diagram for (a) STRATOS 1 and (b) STRATOS 2. aThe STRATOS 1 placebo treatment group is a combined treatment group (placebo every 2 weeks plus placebo every 4 weeks), where the two placebo cohorts were given weights proportional to the number of participants in each cohort. For STRATOS 2, eight participants on tralokinumab every 2 weeks and 11 on placebo were excluded from the full analysis set. bTwo participants were duplicates and were not included in the safety set; these two participants and five who did not have the potential to receive 52 weeks of treatment were not included in the full analysis set. cFive participants did not have the potential to receive 52 weeks of treatment, so were not included in the full analysis set. dOf participants randomly assigned. Republished with permission of Elsevier, from Panettieri et al. [7]; permission conveyed through the Copyright Clearance Center, Inc

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