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Brolucizumab Anti-Drug Antibodies Prevalent in Ophthalmic Patient Population

Anti-brolucizumab ADAs may be a risk factor for intraocular inflammation and retinal occlusive vasculitis in patients treated with brolucizumab.

The presence of brolucizumab anti-drug antibodies (ADAs) was detected with significant prevalence in both patients with and without prior brolucizumab exposure, with stronger, more frequent signals compared with ranibizumab.

These findings suggest anti-brolucizumab ADAs may be a significant risk factor for intraocular inflammation (IOI) and retinal occlusive vasculitis in patients treated with brolucizumab.

“Collectively, our data are in line with previous observations and indicate that both pre-existing and induced brolucizumab ADAs may play a role in IOIs following brolucizumab,” wrote study author Martin Busch, Department of Ophthalmology, University Medical Center Greifswald.

Though rare, severe adverse events may be associated with intravitreal anti-VEGF treatment. Recently, there have been several case reports and case series reporting an increased risk for noninfectious IOI and retinal vasculitis with the use of brolucizumab.

Although the mechanisms behind this increased risk is still unclear, one potential reason may exist in the the form of ADAs to brolucizumab which may play a role in the emergence of IOI and retinal vasculitis. However, it is currently unclear to what extent ADAs to brolucizumab exist in the general ophthalmic patient population.

In the cross-sectional study, investigators sought to measure ADAs to brolucizumab and ranibizumab in the general at-risk population. They additionally looked to describe ADA levels in patients with and without occurrence of IOI events that have received intravitreal injections.

Between January 2020 and February 2021, serum (n = 192) and vitreous (n = 54) samples were collected and analyzed. They were obtained from patients with a range of eye diseases, including neovascular age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, cataract, glaucoma, dry eye disease, macular hold, epiretinal membranes, and intraocular lens (IOL) dislocation.

The serum and vitreous samples were analyzed for immune globulin (Ig) G ADAs to brolucizumab and ranibizumab using indirect enzyme-linked immunosorbent assay (ELISA). Optical density (OD) was read at 450 nm with wavelength correction at 550 nm for ADA level measurements.

In 35 of 192 serum samples (18.2%), there was a notable brolucizumab ADA signal with an OD of >0.1 measured. Investigators noted that some, but not all, of these patients with brolucizumab ADAs had received brolucizumab injections in the past.

A notable brolucizumab ADA signal was more frequent in female patients than in males (females: n = 92, OD >0.1 in 23.9%; males: n = 100 OD >0.1 in 13.0%). The study reported two patients who experienced severe IOI and occlusive retinal vasculitis following intravitreal brolucizumab injection.

Moreover, the study population contained 54 patients who underwent vitrectomy for various medical indications. Investigators found notable brolucizumab ADA signals (OD > 0.1) were slightly less frequent in vitreous samples (n = 7 of 54, 13.0%), compared with the corresponding serum samples (n = 11 of 54, 20.4%).

Of the patients with severe IOI and retinal vasculitis, both had high ODs in the anti-brolucizumab antibody ELISA, indicating high serum titres of IgG ADAs to brolucizumab. Another patient who experienced only moderate IOI following brolucizumab had only low serum ADA titres to brolucizumab, where prompt improvement of IOI was achieved with systemic corticosteroids.

Within the majority of cases (n = 6 of 7, 85.7%), vitreous samples with notable brolucizumab ADA levels were obtained from patients who had never received brolucizumab prior to ADA sampling. Investigators noted a tendency for an increased likelihood of notable vitreal ADA levels in patients with diabetic retinopathy. Across all serum samples, investigators noted the ODs for ADAs to ranibizumab were significantly lower than for ADAs to brolucizumab.

The study, “Anti-drug antibodies to brolucizumab and ranibizumab in serum and vitreous of patients with ocular disease,” was published in Acta Ophthalmologica.