TY - JOUR
T1 - Effect of anti-C5a therapy in a murine model of early/ intermediate dry age-related macular degeneration
AU - Toomey, Christopher B.
AU - Landowski, Michael
AU - Klingeborn, Mikael
AU - Kelly, Una
AU - Deans, John
AU - Dong, Holly
AU - Harrabi, Ons
AU - van Blarcom, Thomas
AU - Yeung, Yik Andy
AU - Grishanin, Ruslan
AU - Lin, John C.
AU - Saban, Daniel R.
AU - Rickman, Catherine Bowes
N1 - Funding Information:
The authors thank Ying Hao and Marybeth Groelle for their expert technical assistance and Rose Matthews and Joan Kalnitsky for their assistance with flow cytometry. We acknowledge Wei Li, Gabriel Berstein, Huilan Gao, and Laird Bloom of Pfizer, Inc., for providing the neutralizing anti-C5a antibody 4C9 and Li Mei for helping engineer the higher-affinity variant of 4C9 used in this study. We also thank Karen Christopherson of Pfizer, Inc., for her insights and helpful suggestions during the initiation and development of this project. Supported by National Eye Institute Grants R01 EY026161 (CBR) and P30 EY005722, T32 GM007171-Medical Scientist Training Program (CBT), an unrestricted grant from Research to Prevent Blindness (to the Duke Eye Center), a grant from the BrightFocus Foundation (MK), and a grant from the Foundation Fighting Blindness (CBR). Pfizer, Inc., owns the intellectual properties of the antibodies described in this study.
Funding Information:
The authors thank Ying Hao and Marybeth Groelle for their expert technical assistance and Rose Matthews and Joan Kalnitsky for their assistance with flow cytometry. We acknowledge Wei Li, Gabriel Berstein, Huilan Gao, and Laird Bloom of Pfizer, Inc., for providing the neutralizing anti-C5a antibody 4C9 and Li Mei for helping engineer the higher-affinity variant of 4C9 used in this study. We also thank Karen Christopherson of Pfizer, Inc., for her insights and helpful suggestions during the initiation and development of this project. Supported by NEI-National Eye Institute Grants R01 EY026161 (CBR) and P30 EY005722, T32 GM007171-Medical Scientist Training Program (CBT), an unrestricted grant from Research to Prevent Blindness (to the Duke Eye Center), a grant from the BrightFocus Foundation (MK), and a grant from the FFB-Foundation Fighting Blindness (CBR). Pfizer, Inc., owns the intellectual properties of the antibodies described in this study.
Publisher Copyright:
© 2018 The Authors.
PY - 2018/2
Y1 - 2018/2
N2 - PURPOSE: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. METHODS: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. RESULTS: Aged Cfh+/-mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. CONCLUSIONS: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/-∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies.
AB - PURPOSE: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. METHODS: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. RESULTS: Aged Cfh+/-mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. CONCLUSIONS: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/-∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies.
KW - Age related macular degeneration
KW - Complement
KW - Immunotherapy
KW - Monocytosis
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U2 - 10.1167/iovs.17-23134
DO - 10.1167/iovs.17-23134
M3 - Article
C2 - 29392311
AN - SCOPUS:85041512023
SN - 0146-0404
VL - 59
SP - 662
EP - 673
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 2
ER -