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Neoplastic Reactions
Published in Gabriella Fabbrocini, Mario E. Lacouture, Antonella Tosti, Dermatologic Reactions to Cancer Therapies, 2019
The induction of NMSC, including SCCs, is also associated with multikinase inhibitors (MKIs) that target RAF, such as sorafenib. Moreover, inflammatory reactions of preexisting AKs have been observed in 10% of patients treated with sorafenib (13–17,22). Finally, recent observations report the induction of KAs and SCCs in patients treated with a monoclonal antibody directed against transforming growth factor beta (anti-TGFβ), fresolimumab. In line with findings for the induction of SCPLs by RAF inhibitors, the authors propose that a crosstalk of TGFβ- and MAPK pathways is the most probable causative molecular mechanism (38).
Advances in biological and targeted therapies for systemic sclerosis
Published in Expert Opinion on Biological Therapy, 2023
Erica Mulcaire-Jones, Andrea Hsiu Ling Low, Robyn Domsic, Michael L Whitfield, Dinesh Khanna
Fresolimumab is a human monoclonal antibody that blocks all isoforms of TGF-β. In an open-label, single-center study patients with early dcSSc (<24 months) received either fresolimumab 1 mg/kg at week 0 and 4 (n = 7) or a single dose of fresolimumab 5 mg/kg at week 0 (n = 8). Skin biopsies were taken intermittently between baseline and week 24. Both groups showed statistically significant decrease in THBS1 gene expression with early biopsies followed by loss of decreased gene expression by week 24. Early skin biopsies showed decreased dermal myofibroblast infiltration. At week 24 there was an increase in mRSS, likely due to fresolimumab wearing off based on known half-life. Gene expression analysis showed downregulation of multiple TGF-β mediated genes. Multiple genes, including THBS1, showed moderate correlation with change in mRSS. Baseline expression of TGF-β regulated genes predicted response to fresolimumab based on biochemical analysis and mRSS. The most common adverse effect was anemia. One patient developed symptoms of heart failure and died 10 days later. Cardiac biopsy prior to death showed significant fibrosis, likely related to underlying SSc and was not thought to be drug related [19].
Antibody-based therapies for idiopathic pulmonary fibrosis
Published in Expert Opinion on Biological Therapy, 2020
Giacomo Sgalla, Mariachiara Flore, Matteo Siciliano, Luca Richeldi
Fresolimumab (GC1008) is a recombinant human monoclonal antibody which acts by inhibiting all the three isoforms of transforming grow factor-beta (TGF-ß), which holds a central role in IPF pathogenesis. Among such isoforms, TGF-β1 is the most implicated in perpetrating the fibrotic process in IPF. In the lungs, TGF-β is produced by a large variety of cell types and secreted in an inactive form; the further activation of TGF-β is mediated by various factors, such as matrix metalloproteinases, integrins, reactive oxygen species that cleavage the latent TGF-β1–binding protein complex. This leads to macrophage and fibroblast recruitment, activation, and proliferation resulting in excessive ECM deposition and collagen production. In these cells, TGF- β also stimulates the expression of several pro-inflammatory and fibrogenic cytokines [9]. As such, downregulation of TGF-β pathway is believed to represent a crucial key for halting the fibrosing process. Back in 2005, a phase I open-label, non-randomized, multicenter, single-dose, dose-escalating study (ClinicalTrials.gov Identifier: NCT00125385) was designed to investigate the safety, tolerability, and pharmacokinetics of fresolimumab administered with a single intravenous infusion in 5 dose groups of patients with IPF. This study was completed but no results have ever been presented, and fresolimumab has not been investigated for IPF ever since.
Drugs in phase I and phase II clinical trials for systemic sclerosis
Published in Expert Opinion on Investigational Drugs, 2020
Melody P. Chung, Lorinda Chung
TGF-β is a key regulator of pathological fibrogenesis in SSc, as the expression of TGF-β-regulated genes is increased in the skin and lungs of patients with SSc [97]. In murine models of SSc, blockade of TGF-β reduced fibrosis leading to an interest in studying anti-TGF-β therapy in humans, but early studies using TGF-β blockade were ineffective [98,99]. In a more recent study, 15 patients with early dcSSc were enrolled in an open-label trial of fresolimumab, a neutralizing antibody that targets TGF-β [97]. Repeat skin biopsies were performed before and after treatment. In patient skin, fresolimumab led to a rapid decrease of TGF-β-regulated biomarker genes and dermal myofibroblast infiltration. Patients treated with fresolimumab had a sharp decline in mRSS, in parallel with a decrease in skin biomarkers. Adverse events included various bleeding episodes such as gastrointestinal bleeding, gingival bleeding and/or epistaxis, subconjunctival hemorrhages (n = 2, 13.3% for each complication), and anemia (n = 10, 66.7%). Fresolimumab is a promising antifibrotic therapy, but further study is warranted regarding its safety and efficacy in treating skin and lung fibrosis.