Pegcetacoplan

Researchers at Trinity College Dublin in Ireland, working with collaborators at the Royal Victoria Eye and Ear Hospital and using population data from the Irish Longitudinal Study on Ageing, have identified that circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration. As per a study published in Cell Reports Medicine, the study found that restoring NK cell activity helped to reduce pathological neovascularization in preclinical models. The work, led by Sarah L. Doyle at Trinity College Dublin, combines human cohort analysis, patient-derived blood cell profiling, donor eye tissue examination, and mouse models to build a case that NK cells AMD patients carry are terminally differentiated, metabolically impaired, and unable to perform the cytotoxic functions that appear necessary for resolving choroidal neovascularization. The study also demonstrates, in two independent mouse models, that adoptive transfer of cytokine-activated NK cells significantly reduces neovascular lesion size, positioning NK cell immunotherapy as a potential complement to existing anti-VEGF approaches. NK cell phenotyping in AMD patients Peripheral blood mononuclear cells from AMD patients and age-matched healthy controls were profiled by flow cytometry. AMD patients showed elevated proportions of CD57-positive terminally differentiated NK cells, reduced CD107a degranulation in response to stimulation, elevated γH2AX marking DNA damage consistent with cellular senescence, and impaired metabolic function as measured by Seahorse XF metabolic stress testing. Taken together, these findings indicate that NK cells in AMD patients are not absent but are functionally exhausted, a distinction the authors frame as central to their mechanistic interpretation. Plasma cytokine profiling from the large TILDA population cohort identified dysregulated inflammatory signatures correlating with AMD severity, with IL-18 levels showing significant association with disease progression. Immunohistochemistry of human donor eyes confirmed the presence of NCR1-positive NK cells in CNV-affected tissue, localized to areas of neovascular lesions, while reanalysis of publicly available single-cell RNA sequencing datasets from human neovascular AMD retinal and choroidal tissue revealed NK cell transcriptional signatures consistent with dysfunction. Mechanism: NK cells and the neovascular endothelium The proposed mechanism centers on the NKG2D receptor axis. Senescent or aberrant retinal endothelial cells upregulate stress ligands including MICA/B and ULBP6, which are recognized by NK cells via NKG2D. In healthy individuals, this recognition triggers degranulation and release of perforin and granzymes, inducing apoptosis in the aberrant endothelial cells and physically limiting neovascular expansion. In AMD patients, the study proposes that terminal differentiation and upregulation of the CXCR4 and CD96 checkpoint axis renders endogenous NK cells unable to execute this cytolytic program, allowing pathological vessel growth to proceed unchecked. In vitro co-culture experiments using human retinal microvascular endothelial cells confirmed that activated NK cells, including the NK92MI cell line and cytokine-primed primary cells, killed target endothelial cells through contact-dependent, perforin-mediated mechanisms. NK cells from AMD patients showed significantly reduced killing capacity relative to healthy donor cells, and cytokine activation with IL-18 and IL-15 partially restored this capacity toward normal levels. Preclinical efficacy in two mouse models In the laser-induced choroidal neovascularization model in C57Bl/6J mice, systemic administration of recombinant IL-18 significantly reduced CNV lesion size relative to PBS controls, with increased NK cell activation at lesion sites confirmed by NCR1-GFP transgenic mouse tracking. Temporal recruitment data showed NK cells infiltrating lesions at defined timepoints post-injury, with endogenous NK cell activity correlating inversely with lesion size. Adoptive transfer of NK cells activated ex vivo with an IL-12, IL-15, and IL-18 cytokine cocktail produced a statistically significant reduction in CNV lesion area relative to PBS controls, with activated cells outperforming non-activated NK cell transfer. The authors then replicated these findings in the JR5558 spontaneous neovascularization mouse model, which develops CNV independently of laser injury, confirming that the therapeutic effect was not an artifact of the injury model. Fluorescein angiography in the JR5558 model indicated reduced vascular permeability following NK cell transfer, suggesting partial restoration of barrier integrity. No overt systemic toxicity was reported at the doses tested, and retinal tissue integrity outside lesion areas was maintained. Competitive and field context The broader neovascular AMD treatment landscape is dominated by anti-VEGF agents, with Roche and Genentech’s Vabysmo (faricimab) representing the most recent approved advance through dual VEGF-A and angiopoietin-2 blockade. For geographic atrophy, the dry form of AMD, Apellis Pharmaceuticals’ Syfovre (pegcetacoplan) and avacincaptad pegol, developed by Iveric Bio and acquired by Astellas Pharma [4503.T], received US FDA approval in 2023, validating the complement pathway as a therapeutic target and demonstrating that innate immune mechanisms in AMD are tractable from a regulatory standpoint. Novartis has also pursued retinal inflammation through brolucizumab and, via its acquisition of Gyroscope Therapeutics, through complement factor I gene therapy for geographic atrophy. No registered clinical trial of an NK cell-based therapy for neovascular AMD was identified in publicly available records, placing this work firmly in the preclinical and translational stage. The closest competitive space is the broader academic literature on peripheral immune cell profiling in AMD, where monocyte subsets and cytokine signatures have been examined, though without producing a dominant clinical platform. The involvement of Roche through its Immunology, Infectious Disease and Ophthalmology Incubator program in funding aspects of this research adds an industry dimension to what is otherwise an academically led program. Trinity College Dublin holds intellectual property on the findings. Translational outlook The study’s translational argument rests on two pillars: that peripheral NK cell profiling could serve as a minimally invasive biomarker of AMD severity or progression, and that cytokine-activated NK cell transfer represents a cell-based immunotherapy approach for neovascular AMD, particularly for patients who respond inadequately to anti-VEGF treatment. The authors note that ex vivo cytokine activation with IL-15 and IL-18 alone, without IL-12, biases NK cells toward cytotoxicity over IFN-γ secretion, which may be relevant for managing systemic inflammatory risk in a clinical setting. Substantial preclinical work remains before any clinical translation. The mouse models used, while mechanistically informative, differ anatomically from the human eye, and the intraperitoneal delivery route used in the mouse experiments would require adaptation for ocular or systemic administration in humans. The study does not report formal IND-enabling toxicology, and the patient cohort sizes for human phenotyping were not specified in the available data. Cross-trial comparisons with anti-VEGF or complement inhibitor efficacy benchmarks are not feasible at this stage. The macular degeneration research field has increasingly recognized that AMD involves systemic immune dysregulation rather than purely local retinal pathology. This study extends that framework by identifying a specific NK cell exhaustion phenotype in patient blood and demonstrating that correcting that dysfunction preclinically can reduce neovascular pathology, providing a mechanistic rationale for further development of NK cell immunotherapy in this indication. Meta description: Trinity College Dublin study identifies exhausted NK cells in AMD patients and shows cytokine-activated NK cell transfer reduces choroidal neovascularization in mice. 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Astellas reported promising results with its stem cell-derived therapy in an age-related eye disease, though data in a handful of high-dose patients in the early-stage study raised questions. The experimental stem cell therapy, called ASP7317, is made from embryonic stem cells, which are differentiated into eye cells key to vision. Those cells are then injected into the eye of the patient in hopes of improving sight in patients with geographic atrophy, an advanced form of age-related macular degeneration that leads to vision loss over time. Astellas currently markets the eye drug Izervay for geographic atrophy, and Izervay and its competitor Syfovre can slow the progression of the disease. But those drugs can’t restore vision that’s already lost, meaning they’re less potent for patients with advanced disease. At one year, patients in the Phase 1b trial who received the low and medium dose of the treatment saw their vision improve by 5.50 and 9.08 letters, respectively, while their untreated eyes got worse. But at the high dose, after six months, there was minimal difference between the treated and untreated eyes. Marci English, Astellas’ head of biopharma and ophthalmology development, pointed to variability in the vision test as well as the small number of high-dose patients as potential reasons for the difference with that group. “I think the jury is still out,” she said, adding that Astellas was waiting for the one-year data on those patients. She said that part of the study’s purpose is also to pick the optimal dose for the therapy. Stem cell-derived therapies are still a niche field, with just a few major drug developers studying the treatments in humans. Bayer’s BlueRock, for instance, is testing a stem cell-derived therapy for Parkinson’s disease in a Phase 3 trial. In Japan, Sumitomo Pharma’s stem cell-based therapy for Parkinson’s received a conditional approval. Some startups are likewise working on stem cell-derived therapies for eye diseases, including Luxa Biotechnology and Genentech-partnered Lineage Cell Therapeutics. The stem cell therapy is also part of Astellas’ broader goal to boost its ophthalmology portfolio. The cell therapy comes from Astellas’ buyout of Ocata Therapeutics a decade ago. More recently, in 2023, Astellas paid about $6 billion to acquire Izervay’s maker, Iveric Bio.