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

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.

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

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

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

Ion exchange chromatography profiles of tralokinumab and mavrilimumab Fab-arm exchange under (a) physiological conditions and (b) non-physiological conditions

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