Dual angiopoietin‐2/VEGF‐A neutralisation prevents vascular leakage, cell death and subretinal macrophage infiltration in mouse models of retinal ischaemia/reperfusion injury and spontaneous CNV
Purpose Explore impact of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) targeting by faricimab on vessel destabilisation and retinal inflammation in 2 mouse models: retinal ischaemia/reperfusion (I/R) injury model to assess vascular permeability, and JR5558 spontaneous ch...
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| Veröffentlicht in: | Acta ophthalmologica (Oxford, England) England), 2022-01, Vol.100 (S267), p.n/a |
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| creator | Canonica, Jérémie Shanmugam, Sumathi Lin, Cheng‐mao Antonetti, David Foxton, Richard Uhles, Sabine Westenkow, Peter Abcouwer, Steve Garcia Garrido, Marina |
| description | Purpose
Explore impact of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) targeting by faricimab on vessel destabilisation and retinal inflammation in 2 mouse models: retinal ischaemia/reperfusion (I/R) injury model to assess vascular permeability, and JR5558 spontaneous choroidal neovascularisation (sCNV) model to investigate inflammation, in the context of phase 2/3 clinical data on faricimab.
Methods
Antibodies against Ang‐2, VEGF‐A, or both (VA2) and IgG (control) were intravitreally injected 2 days before I/R injury in the I/R model. Vascular permeability and ongoing cell death were assessed by retinal FITC‐BSA accumulation and DNA fragmentation assay, respectively, 48h after injury. JR5558 mice were treated intraperitoneally at postnatal days P45, P52 with mouse cross‐reactive tool antibodies to Ang‐2, VEGF‐A, both (VA2) and IgG. Subretinal inflammatory cell (Iba1+, CD45+, CD11b+) infiltration was evaluated by flat‐mount retinal pigment epithelium (RPE)/choroid histology at 1 (PT1), 3 (PT2), and 5 weeks (PT3) post‐treatment.
Results
Post‐I/R injury, VA2 significantly prevented retinal vascular permeability by 64%; anti–VEGF‐A by 37%; anti–Ang‐2 produced no significant change. VA2 significantly reduced ongoing cell death by 47%; VEGF‐A, Ang‐2 alone had no significant effect. In JR5558 mice, VA2, not anti–VEGF‐A or anti–Ang‐2 alone, significantly reduced Iba1+ microglia/macrophages on RPE/choroid and around lesions versus IgG at PT1 and PT2. At PT3, anti–Ang‐2, VA2, not anti–VEGF‐A, showed significant reductions in Iba1+ cells versus IgG. CD45+, CD11b+ cells on RPE/choroid and around lesions were significantly reduced only with VA2 versus IgG.
Conclusions
Dual Ang‐2/VEGF‐A inhibition synergistically prevented retinal vascular leakage, cell death and inflammation in retinal I/R injury and sCNV mouse models, suggesting that vascular leakage, prolonged inflammation are driven by Ang‐2, and supporting recent phase 2/3 clinical data that demonstrated sustained efficacy of faricimab versus intravitreal anti‐VEGF monotarget therapy and extended durability up to every 16 weeks. |
| doi_str_mv | 10.1111/j.1755-3768.2022.199 |
| format | Article |
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Explore impact of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) targeting by faricimab on vessel destabilisation and retinal inflammation in 2 mouse models: retinal ischaemia/reperfusion (I/R) injury model to assess vascular permeability, and JR5558 spontaneous choroidal neovascularisation (sCNV) model to investigate inflammation, in the context of phase 2/3 clinical data on faricimab.
Methods
Antibodies against Ang‐2, VEGF‐A, or both (VA2) and IgG (control) were intravitreally injected 2 days before I/R injury in the I/R model. Vascular permeability and ongoing cell death were assessed by retinal FITC‐BSA accumulation and DNA fragmentation assay, respectively, 48h after injury. JR5558 mice were treated intraperitoneally at postnatal days P45, P52 with mouse cross‐reactive tool antibodies to Ang‐2, VEGF‐A, both (VA2) and IgG. Subretinal inflammatory cell (Iba1+, CD45+, CD11b+) infiltration was evaluated by flat‐mount retinal pigment epithelium (RPE)/choroid histology at 1 (PT1), 3 (PT2), and 5 weeks (PT3) post‐treatment.
Results
Post‐I/R injury, VA2 significantly prevented retinal vascular permeability by 64%; anti–VEGF‐A by 37%; anti–Ang‐2 produced no significant change. VA2 significantly reduced ongoing cell death by 47%; VEGF‐A, Ang‐2 alone had no significant effect. In JR5558 mice, VA2, not anti–VEGF‐A or anti–Ang‐2 alone, significantly reduced Iba1+ microglia/macrophages on RPE/choroid and around lesions versus IgG at PT1 and PT2. At PT3, anti–Ang‐2, VA2, not anti–VEGF‐A, showed significant reductions in Iba1+ cells versus IgG. CD45+, CD11b+ cells on RPE/choroid and around lesions were significantly reduced only with VA2 versus IgG.
Conclusions
Dual Ang‐2/VEGF‐A inhibition synergistically prevented retinal vascular leakage, cell death and inflammation in retinal I/R injury and sCNV mouse models, suggesting that vascular leakage, prolonged inflammation are driven by Ang‐2, and supporting recent phase 2/3 clinical data that demonstrated sustained efficacy of faricimab versus intravitreal anti‐VEGF monotarget therapy and extended durability up to every 16 weeks.</description><identifier>ISSN: 1755-375X</identifier><identifier>EISSN: 1755-3768</identifier><identifier>DOI: 10.1111/j.1755-3768.2022.199</identifier><language>eng</language><publisher>Malden: Wiley Subscription Services, Inc</publisher><subject>Angiopoietin ; Animal models ; Apoptosis ; CD11b antigen ; CD45 antigen ; Cell death ; DNA fragmentation ; Epithelium ; Immunoglobulin G ; Infiltration ; Inflammation ; Ischemia ; Leakage ; Macrophages ; Microglia ; Permeability ; Reperfusion ; Retina ; Retinal pigment epithelium ; Vascular endothelial growth factor</subject><ispartof>Acta ophthalmologica (Oxford, England), 2022-01, Vol.100 (S267), p.n/a</ispartof><rights>2022 The Authors © 2022 Acta Ophthalmologica Scandinavica Foundation</rights><rights>Copyright © 2022 Acta Ophthalmologica Scandinavica Foundation</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1739-47f5b7fef6f427e14647dce82f675d630a698b01c442ad43359c6ee5dec31f343</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1755-3768.2022.199$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45575,46833</link.rule.ids></links><search><creatorcontrib>Canonica, Jérémie</creatorcontrib><creatorcontrib>Shanmugam, Sumathi</creatorcontrib><creatorcontrib>Lin, Cheng‐mao</creatorcontrib><creatorcontrib>Antonetti, David</creatorcontrib><creatorcontrib>Foxton, Richard</creatorcontrib><creatorcontrib>Uhles, Sabine</creatorcontrib><creatorcontrib>Westenkow, Peter</creatorcontrib><creatorcontrib>Abcouwer, Steve</creatorcontrib><creatorcontrib>Garcia Garrido, Marina</creatorcontrib><title>Dual angiopoietin‐2/VEGF‐A neutralisation prevents vascular leakage, cell death and subretinal macrophage infiltration in mouse models of retinal ischaemia/reperfusion injury and spontaneous CNV</title><title>Acta ophthalmologica (Oxford, England)</title><description>Purpose
Explore impact of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) targeting by faricimab on vessel destabilisation and retinal inflammation in 2 mouse models: retinal ischaemia/reperfusion (I/R) injury model to assess vascular permeability, and JR5558 spontaneous choroidal neovascularisation (sCNV) model to investigate inflammation, in the context of phase 2/3 clinical data on faricimab.
Methods
Antibodies against Ang‐2, VEGF‐A, or both (VA2) and IgG (control) were intravitreally injected 2 days before I/R injury in the I/R model. Vascular permeability and ongoing cell death were assessed by retinal FITC‐BSA accumulation and DNA fragmentation assay, respectively, 48h after injury. JR5558 mice were treated intraperitoneally at postnatal days P45, P52 with mouse cross‐reactive tool antibodies to Ang‐2, VEGF‐A, both (VA2) and IgG. Subretinal inflammatory cell (Iba1+, CD45+, CD11b+) infiltration was evaluated by flat‐mount retinal pigment epithelium (RPE)/choroid histology at 1 (PT1), 3 (PT2), and 5 weeks (PT3) post‐treatment.
Results
Post‐I/R injury, VA2 significantly prevented retinal vascular permeability by 64%; anti–VEGF‐A by 37%; anti–Ang‐2 produced no significant change. VA2 significantly reduced ongoing cell death by 47%; VEGF‐A, Ang‐2 alone had no significant effect. In JR5558 mice, VA2, not anti–VEGF‐A or anti–Ang‐2 alone, significantly reduced Iba1+ microglia/macrophages on RPE/choroid and around lesions versus IgG at PT1 and PT2. At PT3, anti–Ang‐2, VA2, not anti–VEGF‐A, showed significant reductions in Iba1+ cells versus IgG. CD45+, CD11b+ cells on RPE/choroid and around lesions were significantly reduced only with VA2 versus IgG.
Conclusions
Dual Ang‐2/VEGF‐A inhibition synergistically prevented retinal vascular leakage, cell death and inflammation in retinal I/R injury and sCNV mouse models, suggesting that vascular leakage, prolonged inflammation are driven by Ang‐2, and supporting recent phase 2/3 clinical data that demonstrated sustained efficacy of faricimab versus intravitreal anti‐VEGF monotarget therapy and extended durability up to every 16 weeks.</description><subject>Angiopoietin</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>CD11b antigen</subject><subject>CD45 antigen</subject><subject>Cell death</subject><subject>DNA fragmentation</subject><subject>Epithelium</subject><subject>Immunoglobulin G</subject><subject>Infiltration</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>Leakage</subject><subject>Macrophages</subject><subject>Microglia</subject><subject>Permeability</subject><subject>Reperfusion</subject><subject>Retina</subject><subject>Retinal pigment epithelium</subject><subject>Vascular endothelial growth factor</subject><issn>1755-375X</issn><issn>1755-3768</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqNkcFu1DAQhqOKSpSWN-BgiSu7GyeOkxxXS1sqVfRQqLhZs86469RrBzsu2huPwFP1QXgSHEJ7xgd7ZM33aew_y97RfEnTWvVLWlfVoqx5syzyoljStj3KTl4uX73U1bfX2ZsQ-jznlHN2kj19jGAI2HvtBqdx1Pb3z1_F6u788iIVa2Ixjh6MDjBqZ8ng8RHtGMgjBBkNeGIQHuAePxCJxpAOYdwlXUdC3PpJl-x7kN4Nu9RFtFXaJOFfmbZk72LAtHdoAnGKPCM6yB3gXsPK44BexTADffSHWT84O4LFxJPN57uz7FiBCfj233mafb04_7L5tLi-ubzarK8XktZlu2C1qra1QsUVK2qkjLO6k9gUitdVx8sceNtscyoZK6BjZVm1kiNWHcqSqpKVp9n72Tt49z1iGEXvok8TB1GkH6U0bzhPXWzuSu8OwaMSg9d78AdBczElJnoxBSKmcMSUmEiJJayZsR_a4OG_GLG-uZ3QPwJOoWk</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Canonica, Jérémie</creator><creator>Shanmugam, Sumathi</creator><creator>Lin, Cheng‐mao</creator><creator>Antonetti, David</creator><creator>Foxton, Richard</creator><creator>Uhles, Sabine</creator><creator>Westenkow, Peter</creator><creator>Abcouwer, Steve</creator><creator>Garcia Garrido, Marina</creator><general>Wiley Subscription Services, Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>202201</creationdate><title>Dual angiopoietin‐2/VEGF‐A neutralisation prevents vascular leakage, cell death and subretinal macrophage infiltration in mouse models of retinal ischaemia/reperfusion injury and spontaneous CNV</title><author>Canonica, Jérémie ; Shanmugam, Sumathi ; Lin, Cheng‐mao ; Antonetti, David ; Foxton, Richard ; Uhles, Sabine ; Westenkow, Peter ; Abcouwer, Steve ; Garcia Garrido, Marina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1739-47f5b7fef6f427e14647dce82f675d630a698b01c442ad43359c6ee5dec31f343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Angiopoietin</topic><topic>Animal models</topic><topic>Apoptosis</topic><topic>CD11b antigen</topic><topic>CD45 antigen</topic><topic>Cell death</topic><topic>DNA fragmentation</topic><topic>Epithelium</topic><topic>Immunoglobulin G</topic><topic>Infiltration</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>Leakage</topic><topic>Macrophages</topic><topic>Microglia</topic><topic>Permeability</topic><topic>Reperfusion</topic><topic>Retina</topic><topic>Retinal pigment epithelium</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Canonica, Jérémie</creatorcontrib><creatorcontrib>Shanmugam, Sumathi</creatorcontrib><creatorcontrib>Lin, Cheng‐mao</creatorcontrib><creatorcontrib>Antonetti, David</creatorcontrib><creatorcontrib>Foxton, Richard</creatorcontrib><creatorcontrib>Uhles, Sabine</creatorcontrib><creatorcontrib>Westenkow, Peter</creatorcontrib><creatorcontrib>Abcouwer, Steve</creatorcontrib><creatorcontrib>Garcia Garrido, Marina</creatorcontrib><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Acta ophthalmologica (Oxford, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Canonica, Jérémie</au><au>Shanmugam, Sumathi</au><au>Lin, Cheng‐mao</au><au>Antonetti, David</au><au>Foxton, Richard</au><au>Uhles, Sabine</au><au>Westenkow, Peter</au><au>Abcouwer, Steve</au><au>Garcia Garrido, Marina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual angiopoietin‐2/VEGF‐A neutralisation prevents vascular leakage, cell death and subretinal macrophage infiltration in mouse models of retinal ischaemia/reperfusion injury and spontaneous CNV</atitle><jtitle>Acta ophthalmologica (Oxford, England)</jtitle><date>2022-01</date><risdate>2022</risdate><volume>100</volume><issue>S267</issue><epage>n/a</epage><issn>1755-375X</issn><eissn>1755-3768</eissn><abstract>Purpose
Explore impact of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) targeting by faricimab on vessel destabilisation and retinal inflammation in 2 mouse models: retinal ischaemia/reperfusion (I/R) injury model to assess vascular permeability, and JR5558 spontaneous choroidal neovascularisation (sCNV) model to investigate inflammation, in the context of phase 2/3 clinical data on faricimab.
Methods
Antibodies against Ang‐2, VEGF‐A, or both (VA2) and IgG (control) were intravitreally injected 2 days before I/R injury in the I/R model. Vascular permeability and ongoing cell death were assessed by retinal FITC‐BSA accumulation and DNA fragmentation assay, respectively, 48h after injury. JR5558 mice were treated intraperitoneally at postnatal days P45, P52 with mouse cross‐reactive tool antibodies to Ang‐2, VEGF‐A, both (VA2) and IgG. Subretinal inflammatory cell (Iba1+, CD45+, CD11b+) infiltration was evaluated by flat‐mount retinal pigment epithelium (RPE)/choroid histology at 1 (PT1), 3 (PT2), and 5 weeks (PT3) post‐treatment.
Results
Post‐I/R injury, VA2 significantly prevented retinal vascular permeability by 64%; anti–VEGF‐A by 37%; anti–Ang‐2 produced no significant change. VA2 significantly reduced ongoing cell death by 47%; VEGF‐A, Ang‐2 alone had no significant effect. In JR5558 mice, VA2, not anti–VEGF‐A or anti–Ang‐2 alone, significantly reduced Iba1+ microglia/macrophages on RPE/choroid and around lesions versus IgG at PT1 and PT2. At PT3, anti–Ang‐2, VA2, not anti–VEGF‐A, showed significant reductions in Iba1+ cells versus IgG. CD45+, CD11b+ cells on RPE/choroid and around lesions were significantly reduced only with VA2 versus IgG.
Conclusions
Dual Ang‐2/VEGF‐A inhibition synergistically prevented retinal vascular leakage, cell death and inflammation in retinal I/R injury and sCNV mouse models, suggesting that vascular leakage, prolonged inflammation are driven by Ang‐2, and supporting recent phase 2/3 clinical data that demonstrated sustained efficacy of faricimab versus intravitreal anti‐VEGF monotarget therapy and extended durability up to every 16 weeks.</abstract><cop>Malden</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1111/j.1755-3768.2022.199</doi><tpages>0</tpages></addata></record> |
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| subjects | Angiopoietin Animal models Apoptosis CD11b antigen CD45 antigen Cell death DNA fragmentation Epithelium Immunoglobulin G Infiltration Inflammation Ischemia Leakage Macrophages Microglia Permeability Reperfusion Retina Retinal pigment epithelium Vascular endothelial growth factor |
| title | Dual angiopoietin‐2/VEGF‐A neutralisation prevents vascular leakage, cell death and subretinal macrophage infiltration in mouse models of retinal ischaemia/reperfusion injury and spontaneous CNV |
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