Real World Immunogenicity of Benralizumab

Abstract

Background Despite biomarker-guided initiation, non- or loss of response to biologic therapy occurs in a minority of patients with severe asthma. In cases of treatment failure, it is important to understand why treatment has failed as this can guide future biologic choices. The formation of anti-drug antibodies (ADA) can occur with all biologics and is a potential cause of treatment failure, however, immunoassays created by drug-manufacturers during the development program are seldom made available for routine clinical testing. Methods We developed the GloBody platform to rapidly generate, manufacturer-independent immunoassays. The sequences of a single chain variable fragment encoding the monoclonal antibody variable region, dual nanolucifearase reporters and a histidine tag are synthesized, expressed in bacteria and purified. The GloBodies are bound by benralizumab-specific ADA in plasma/serum and complexes are captured by immobilized protein G and quantitated using luminometry, following the addition of nanoluciferase substrate. Peripheral blood samples were collected from 74 patients with severe asthma and 15 healthy controls. The severe asthma patients were purposively sampled to include those with a range of clinical responses to Benralizumab. The severe asthma patients were categorized as Benralizumab naive (n=27) or Benralizumab exposed (n=47) with the latter further categorized as having had a good response (n=17), borderline response (n=8), poor response (n=16) or poor response with development of blood eosinophils >0.1x109/L whilst on Benralizumab (n=6). Results Preliminary blinded analysis identified three individuals positive for ADAs. All three patients were in the subgroup of those who had had a poor response with development of blood eosinophils >0.1x109/L whilst on Benralizumab. Conclusion This platform further demonstrated its versatility and can be used to monitor ADA to any antibody-based therapeutic, where the protein sequence is known. Discussion ADAs to Benralizumab can be detected in patients with non-/loss of response to the biologic and are useful to identify this as the cause of treatment failure, as opposed to other causes such as non-adherence to homecare self-administration, thereby guiding future biologics choices. Clinically validated tests for ADAs would be beneficial in clinic.