Antibody pamrevlumab blocks fibrotic drivers of lens clouding in pediatric cells

One of the most common setbacks after cataract surgery may have just met an unexpected challenger. In a randomized, controlled laboratory study conducted at the Central Biomedical Laboratory of the Faculty of Medicine, Universitas Brawijaya between September 2024 and November 2025, researchers tested pamrevlumab, a fully human monoclonal antibody that targets connective tissue growth factor, against the cellular processes that drive posterior capsular opacification, the clouding of the lens capsule that can return after cataract removal. Working with lens epithelial cells harvested from pediatric cataract patients, the team reports that the antibody suppressed the key fibrotic hallmarks that make this complication so stubborn, including collagen type I production, cell migration and cell proliferation, while leaving a parallel signaling pathway untouched.

Posterior capsular opacification arises when residual lens epithelial cells left behind after surgery proliferate, migrate and undergo epithelial-mesenchymal transition, a program that transforms them into matrix-producing, scar-forming cells. The result is a fibrotic membrane that creeps across the visual axis. Transforming growth factor-β2 is a central conductor of this process, switching on intracellular cascades such as β-catenin and ERK that govern extracellular matrix synthesis, proliferation and migration. Among the downstream mediators, connective tissue growth factor acts as an amplifier of the fibrotic response, promoting collagen production and sustaining the scar-forming phenotype. Collagen type I is the principal structural component of the pathological membrane, and its excessive deposition is what physically manifests as the opaque scar that obscures vision.

Pamrevlumab, also known by its investigational designation FG-3019, has already shown antifibrotic activity in multiple fibrotic diseases and has advanced through late-stage clinical testing in other contexts. What remained unclear was how the antibody behaves in human lens epithelial cells driven into fibrosis by TGF-β2. The new study is described as the first to evaluate the drug in a clinically relevant setting for this condition, using primary human pediatric lens epithelial cells rather than immortalized cell lines, a choice made because pediatric cases tend to produce a particularly aggressive fibrotic response and because primary cells better recapitulate that behavior.

The experimental design was deliberately simple and controlled. Cells isolated from anterior lens capsules obtained during pediatric cataract surgery were allocated to five parallel conditions: a negative control grown in medium alone, a positive control stimulated with 10 nanograms per milliliter of TGF-β2, and three groups pretreated with pamrevlumab at 50, 100 or 150 micrograms per milliliter for one hour before the TGF-β2 exposure. At least four biological replicates per group were used, each derived from a different pediatric donor culture to capture the real biological variability among patients. The researchers measured β-catenin nuclear translocation, ERK1/2 phosphorylation, collagen type I expression, wound-healing migration and proliferation at specific time points, using immunofluorescence microscopy, a scratch-based wound assay and direct morphological cell counting rather than metabolic assays, which the authors note can overestimate viable cell numbers.

The signaling results revealed a striking selectivity. TGF-β2 exposure increased β-catenin nuclear translocation at 18 hours, confirming activation of the Wnt and β-catenin pathway. Pamrevlumab pretreatment produced a significant inhibitory effect at 24 hours, with the 100 and 150 microgram per milliliter doses significantly reducing nuclear β-catenin compared with the TGF-β2-only group. The analysis also uncovered a significant inverse dose-response relationship, with higher doses producing stronger suppression, and the strongest inhibition occurring at 24 hours with the 100 microgram per milliliter dose. By 48 hours, however, β-catenin translocation rebounded across all groups, and although the 100 microgram per milliliter group remained numerically lower than the positive control, the difference was no longer statistically significant, pointing to an efficacy window that peaks at 24 hours.

Equally notable was what did not change. ERK phosphorylation showed no differences between pamrevlumab-treated cells and controls at 18, 24 or 48 hours, and even the highest dose of 150 micrograms per milliliter failed to reduce ERK phosphorylation relative to the positive control. All conditions followed the same temporal profile, peaking at 18 hours, dipping at 24 hours and rising again at 48 hours, with no separation between treated and untreated cells. This means that in primary human lens epithelial cells, the antifibrotic action of pamrevlumab operates through the β-catenin pathway independently of the ERK mitogenic cascade, a selectivity the authors suggest may in principle allow pathological fibrosis to be targeted while broadly preserving other cellular signaling.

The functional consequences followed the signaling story. TGF-β2 significantly upregulated collagen type I at 18 and 24 hours, with expression peaking at 24 hours, and pamrevlumab pretreatment at 100 and 150 micrograms per milliliter suppressed this elevation, returning collagen levels to values comparable with untreated controls by the 24-hour mark. Regression analysis estimated a reduction of approximately 608.40 arbitrary units in collagen type I expression for every 1 microgram per milliliter increase in pamrevlumab dose, a relationship the authors describe as strongly dose-dependent. Structural equation modeling confirmed that the dose of pamrevlumab, rather than incubation time, was the primary driver of collagen reduction, although the inhibitory effect on collagen became statistically nonsignificant by 48 hours, reinforcing the idea of a therapeutic window within the first day after exposure.

Migration and proliferation, the two behaviors that allow residual cells to repopulate the posterior capsule, were also restrained. Baseline wound areas were uniform across groups at the start of the assay, and pamrevlumab significantly retarded TGF-β2-induced migration from 24 to 72 hours, with the 100 microgram per milliliter dose providing the most consistent inhibition by maintaining a significantly larger residual wound area compared with the stimulated group throughout the observation period. Proliferation was significantly suppressed at 24 and 48 hours, with a significant correlation between dose and proliferative activity, and the antibody effectively neutralized the mitogenic drive of TGF-β2, returning cell counts toward baseline levels. The path analysis added an important nuance: the direct effect of pamrevlumab on proliferation was not statistically significant, but its indirect effect, mediated through the inhibition of migration, was, indicating that the antiproliferative capacity of the drug is largely achieved by first limiting the migratory potential of the cells.

The authors interpret these findings as evidence that connective tissue growth factor is not merely one growth factor among many but a master regulator of the coordinated cellular responses required for opacification to progress. They propose a plausible mechanism: CTGF amplifies TGF-β2 signaling by interacting with the LRP6 coreceptor, which stabilizes cytoplasmic β-catenin and facilitates its entry into the nucleus, and pamrevlumab likely disrupts this crosstalk, preventing the β-catenin-dependent transcription of genes involved in epithelial-mesenchymal transition and extracellular matrix production. Notably, the selective modulation may offer an advantage over approaches that aim to eliminate all residual lens epithelial cells, which have historically raised concerns about capsular instability, because the antibody appears to suppress profibrotic signaling without blanket suppression of cellular activity.

Important caveats temper the enthusiasm. This was an in vitro system that cannot reproduce the postsurgical capsular bag environment, including biomechanical forces and blood-aqueous barrier influences, and the study did not assess long-term capsular integrity, ocular safety, pharmacokinetics, corneal epithelial recovery or postoperative wound repair. The observed effects were largely confined to a 24-to-48-hour window, and the absence of ERK modulation may partly reflect limited early sampling that could miss transient activation peaks. Only collagen type I was used as the functional fibrotic marker, without broader profiling of epithelial-mesenchymal transition markers such as α-SMA, fibronectin, vimentin or E-cadherin. The authors also caution that pediatric-derived cells may differ from adult cells in proliferative capacity, that validation with adult-derived cells and human capsular bag systems would be needed before wider extrapolation, and that the results should not be read as advocating replacement of established clinical strategies such as laser capsulotomy. Rather, the work offers an early, hypothesis-generating preclinical basis for CTGF-targeted prevention of posterior capsular opacification, and suggests that if single-dose blockade provides only transient suppression, future clinical use may require sustained-release intraocular delivery systems or redosing approaches.

Subject of Research: Preclinical testing of the anti-CTGF antibody pamrevlumab for preventing posterior capsular opacification in primary pediatric lens epithelial cells

Article Title: Pamrevlumab inhibits posterior capsule opacification via selective CTGF /β-catenin axis modulation and collagen-1 suppression in primary pediatric LECs

Article References: Wulandari, L. R., Kautsarani, I., Rofiq, R., Prabowo, E. D., Sujuti, H., Permatasari, H. K., & Winarsih, S. (2026). Pamrevlumab inhibits posterior capsule opacification via selective CTGF/β-catenin axis modulation and collagen-1 suppression in primary pediatric LECs. Pharmacia, 73, Article e190953. https://doi.org/10.3897/pharmacia.73.e190953

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e190953

Keywords: posterior capsular opacification, pamrevlumab, CTGF, lens epithelial cells, TGF-β2, β-catenin, collagen type I, epithelial-mesenchymal transition, pediatric cataract, fibrosis, in vitro study, ophthalmology