Targeting TGF-β for treatment of osteogenesis imperfecta

Abstract

BACKGROUND Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI. METHODS Histology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS OI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSION Increased TGF-β signaling is a driver pathogenic mechanism in OI. Anti–TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION ClinicalTrials.gov NCT03064074. FUNDING Brittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

A multi‐model approach to predict efficacious clinical dose for an anti‐TGF‐β antibody (GC2008) in the treatment of osteogenesis imperfecta

“…Figure 3 shows the PK/ BMD dynamics, along with the respective BMD data for single dose of 1 and 4 mg/kg Fresolimumab (GC1008), in patients with OI. 19 Parameters of the PD model were fit to the BMD data after administration of 1 (Figure 3a) and 4 mg/kg (Figure 3b) Fresolimumab (GC1008). For BMD, administration of 1 mg/kg had minimal effect on the dynamics, as shown in Figure 3a.…”

“…Detailed description of the preclinical and clinical PK/PD data used in this work were published previously and are briefly discussed here. 6,16,17,[19][20][21] Summaries of the available PK/PD data used in our multimodel approach are shown in Table 1. GC2008 is a second generation human anti-TGF-β, differing only by a single amino acid substitution in the heavy chain (S228P) of GC1008.…”

“…22 Due to the low number of BMD data (4 subjects), their sparsity, and their high variability, the E max /EC 50 parameters of the PD model were optimized according to the average BMD value for each timepoint, whereas k in /k out were set based on bone turnover, and BMD baseline in humans. After informing the PD-related parameters with the available BMD data, 19 Fresolimumab (GC1008) PK was replaced by the two-compartment PK model of GC2008 (Figure S1) and based on the PK/PD relationship informed by Fresolimumab (GC1008), the model was used to provide predictions for the GC2008 dose/response (BMD) relationship and ultimately evaluate the dose that will result in a 5% increase in BMD. Population PK analysis of Fresolimumab (GC1008) and GC2008 was performed using NONMEM and Monolix, respectively.…”

“…Interestingly, Grafe et al 6 showed that excessive TGF-β signaling occurs in OI and treatment with 1D11 corrects the bone phenotype and improves the lung abnormalities in OI mice. In humans, Fresolimumab (GC1008), a human anti-TGF-β antibody with similar affinity and epitope binding as 1D11, has been tested in a small number of patients and initial results indicated a potential disease-specific therapy with dose-dependent effects on bone mineral density (BMD), [16][17][18][19] which is an accepted clinical end point in numerous clinical studies to date (https:// clini caltr ials.gov/ct2/show/NCT03 064074, https://clini caltr ials.gov/ct2/show/NCT00 063479, https://clini caltr ials.gov/ct2/show/NCT05 125809, and https://clini caltr ials. gov/ct2/show/NCT03 638128).…”

Roles of tumor-associated neutrophils in tumor metastasis and its clinical applications

“…However, further randomized clinical studies are warranted to validate the potential use of TGF-β in clinical practice. Additionally, fresolimumab was well tolerated and used in participants with osteogenesis imperfecta (OI) type IV, as well as a TGF-β-neutralizing antibody (Song et al, 2022). In phase I/II trials, fresolimumab was shown to have an acceptable safety profile and favorable systemic immune response in patients with melanoma, renal cell carcinoma (Lacouture et al, 2015), and metastatic breast cancer Frontiers in Cell and Developmental Biology frontiersin.org (Formenti et al, 2018).…”