A Comparative Study With ING-006, Nintedanib, Nerandomilast and Bexotegrast Using the In Vivo CAM-Patient-Derived IPF Model
Bibliographic record
Abstract
Abstract RATIONALE: The chick embryo chorioallantoic membrane (CAM)-IPF model allows the culture of idiopathic pulmonary fibrosis (IPF) tissue or fibroblast xenografts with an engraftment success rate of over 90%. Immunohistochemical analysis shows that xenografts derived from fibroblasts mimic fibroblastic foci. In addition, the assay preserves the microenvironment and histopathological characteristics of IPF lung tissue xenografts and treatment response, providing a predictive model of antifibrotic drug efficacy. ING-006 is a novel oral GPR40 agonist/GPR84 antagonist with potent antifibrotic activity in lung and liver models. This study was designed to evaluate the antifibrotic activity of ING-006 compared to nintedanib, and drugs in late-stage clinical development, nerandomilast (BI-1015550) and bexotegrast (PLN-74809) in primary IPF-lung fibroblasts and an in vivo patient-derived CAM-IPF model. METHODS: TGFβ-stimulated primary lung fibroblasts from IPF patients were incubated in the presence or absence of antifibrotics and the expression of fibrotic genes (COL1A1, COL3A1, ACTA2 (α-SMA), CTGF, SERPINE1 and FN1) was evaluated. Fragments of fresh human IPF lung tissue were implanted and cultured on the CAM and treated with the antifibrotic compounds from day 2 to day 7 post-implantation. Xenografts were harvested for histological analysis an immunohistochemistry and qPCRS were performed.RESULTS: Antifibrotic compounds effectively reduced fibrotic gene expression (COL1A1, COL3A1, ACTA2, CTGF, SERPINE1 and FN1) in TGFβ-activated IPF fibroblasts, with ING-006 showing the highest efficacy, followed by bexotegrast and nerandomilast. ING-006 exerts its activity by acting through GPR84, as demonstrated by the lack of inhibition of CTGF expression in GPR84 knockdown fibroblasts. ING-006 also demonstrates superior inhibitory activity over fezagepras (formerly PBI-4050) in ZQ-16 stimulated-pErK lung fibroblasts as well as through inhibition of fibrotic gene expression. In CAM-IPF xenografts, where fibrosis is already implanted, a single low dose of ING-006 (10ug) induced a significant reduction in collagen area, while no significant antifibrotic activity was observed with nintedanib, nerandomilast or bexotegrast. In addition, when used in combination treatment, ING-006 showed synergistic activity with low dose nerandomilast (10ug) and additive activity with high dose bexotegrast (50ug).CONCLUSION: CAM-IPF is an efficient method to predict antifibrotic activity. Among other compounds currently used or under investigation for IPF treatment, ING-006 shows superior antifibrotic activity in fibroblasts and lung tissue xenografts from IPF patients, making it a promising candidate for IPF treatment.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".