| Autor: |
Karle AC; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Wrobel MB; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Koepke S; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Gutknecht M; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Gottlieb S; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Christen B; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Rubic-Schneider T; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Pruimboom-Brees I; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Leber XC; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Scharenberg M; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Maciejewski B; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Turner O; Novartis Institutes for BioMedical Research, East Hanover, NJ 07960, USA., Saravanan C; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Huet F; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Littlewood-Evans A; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland., Clemens A; Medical Affairs Region Europe, Novartis Pharma AG, Basel CH-4056, Switzerland., Grosskreutz CL; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Kearns JD; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Mehan P; TRD Biologics & CGT, Novartis Pharma AG, Basel CH-4056, Switzerland., Schmouder RL; Novartis Institutes for BioMedical Research, East Hanover, NJ 07960, USA., Sasseville V; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Brees D; Novartis Institutes for BioMedical Research, Basel CH-4056, Switzerland. |
| Abstrakt: |
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. |
