Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events.
Anette C KarleMatthias B WrobelStephan KoepkeMichael GutknechtSascha GottliebBrigitte ChristenTina Rubic-SchneiderIngrid Pruimboom-BreesXavier Charles LeberMeike ScharenbergBenjamin MaciejewskiOliver C TurnerChandrassegar SaravananFrançois HuetAmanda Littlewood-EvansAndreas ClemensCynthia L GrosskreutzJeffrey D KearnsPawan MehanRobert L SchmouderVito SassevilleDominique BreesPublished in: Science translational medicine (2023)
In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.
Keyphrases
- mycobacterium tuberculosis
- immune response
- vascular endothelial growth factor
- age related macular degeneration
- diabetic retinopathy
- optical coherence tomography
- clinical trial
- clinical practice
- optic nerve
- early stage
- end stage renal disease
- combination therapy
- endothelial cells
- randomized controlled trial
- stem cells
- dendritic cells
- toll like receptor
- inflammatory response
- ejection fraction
- drug delivery
- prognostic factors
- cancer therapy
- electronic health record
- cell therapy
- peritoneal dialysis
- smoking cessation
- adverse drug