Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus

Abstract

Summary This study's objective was to assess the effects of PD‐0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony‐stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD‐0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre‐ and post‐treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14+ CD16+ monocytes, urinary N‐terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater‐than‐dose‐proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14+ CD16+ cells, uNTX, ALT, AST and CK levels at most time‐points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between‐group differences were seen in CLASI. Patients receiving PD‐0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD‐0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end‐points.

Liver-Chip: Reproducing Human and Cross-Species Toxicities

“…This was confirmed in Liver-Chip where treatment with JNJ-1 caused a depletion in Kupffer cells accompanied by decreases in cytokines. Transaminase elevations have been observed with other agents that inhibit CSF-1/CSF-1R (45). Kupffer cells depend on CSF-1 for viability and evidence has been presented that transaminase elevations are downstream of Kupffer cell depletion and possibly a consequence of a role for Kupffer cells in transaminase clearance (26).…”

Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

“…JPET # 254128 28 difference in efficacy versus placebo (Genovese et al, 2015). Likewise, a phase 1b study of PD-0360324 (a human IgG2 monoclonal antibody that inhibits CSF-1 binding to CSF-1R) in patients with cutaneous lupus erythematosus (N = 28) demonstrated target engagement, but no therapeutic effects were observed (Masek-Hammerman et al, 2016). The most promising effects of CSF-1/CSF-1R inhibition have been reported in patients with PVNS, with several studies demonstrating clear therapeutic benefits (i.e., tumor volume regression, objective response, complete response, and symptomatic improvement) (Cassier et al, 2012;Stacchiotti et al, 2013;Cassier et al, 2015;Tap et al, 2015).…”

“…An antibody against CSF-1, PD-0360324, has been tried in RA (ClinicalTrials.gov NCT00550355), lupus erythematosus (Masek-Hammerman et al, 2016), and pulmonary sarcoidosis (ClinicalTrials.gov NCT01732211). In these studies, the AEs of periorbital edema or swelling and raised circulating enzyme or CK levels were observed (Cassier et al, 2012;Cassier et al, 2015;Genovese et al, 2015;Tap et al, 2015;Masek-Hammerman et al, 2016;Cannarile et al, 2017). These AEs appear to be typical of agents targeting the CSF-1 pathway and have hindered the clinical development of therapies in this area.…”

Early risk prognosis of free-flap transplant failure by quantitation of the macrophage colony-stimulating factor in patient plasma using 2-dimensional liquid-chromatography multiple reaction monitoring-mass spectrometry

“…Suitable medication may make use of either M-CSF-targeting antibodies or M-CSF receptor-targeting antibodies which are already in use or are being tested in clinical studies for other indications. [58–60] In conjunction with free flap transplantation, anti-M-CSF treatment may be advised after determination of individual M-CSF concentrations once levels are found above threshold. It remains to be seen in future clinical trials whether a positive effect on free flap perfusion and reduced cases of complications can be achieved as outcome of medication-based intervention.…”