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

Abstract

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1-dependent mechanisms are also involved in bloodborne protein clearance.Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5× the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. The majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free/unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK across doses from 0.01 to 20 mg/kg, with faster apparent elimination at lower doses or concentrations; this was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.

Detection of CSF1 rearrangements deleting the 3′ UTR in tenosynovial giant cell tumors

“…Similarly, deletions or truncations of the 3′ UTR of CCND1 have been reported to lead to cyclin D1 overexpression in mantle cell lymphoma via deletion of miRNA target sites . It is thus likely that CSF1 alterations removing this region would likewise result in decreased mRNA degradation in tenosynovial giant cell tumors and increased levels of functional CSF1 cytokine‐mediated activation of monocyte‐macrophage CSF1R, explaining the recent success of therapies targeting the CSF1‐CSF1R axis in this disease …”

“…45,46 It is thus likely that CSF1 alterations removing this region would likewise result in decreased mRNA degradation in tenosynovial giant cell tumors and increased levels of functional CSF1 cytokine-mediated activation of monocyte-macrophage CSF1R, explaining the recent success of therapies targeting the CSF1-CSF1R axis in this disease. [9][10][11][12]32 Earlier studies of tenosynovial giant cell tumors suggested that promoter swapping with COL6A3 led to CSF1 upregulation via transcriptional control under the strong collagen promoter, analogous to the mechanism of PDGFB overexpression when fused to the COL1A1 promoter in dermatofibrosarcoma protuberans. 47 Quite recently, CBL mutations were identified in 35% of tenosynovial giant cell tumors.…”

“…The presence of dysregulation of CSF1‐CSF1R (a.k.a. macrophage colony‐stimulating factor receptor, the product of the c‐fms protooncogene) signaling has inspired the clinical use of receptor‐tyrosine kinase inhibition to treat tenosynovial giant cell tumors, and prompted clinical trials of selective CSF1 and CSF1‐receptor inhibitors that have shown promising activity as a targeted therapy for this disease (eg, NCT01643850, http://clinicaltrials.gov), as well as in other tumors that over‐express CSF1 …”

“…macrophage colony-stimulating factor receptor, the product of the c-fms protooncogene) signaling has inspired the clinical use of receptor-tyrosine kinase inhibition to treat tenosynovial giant cell tumors, 8 and prompted clinical trials of selective CSF1 and CSF1-receptor inhibitors that have shown promising activity as a targeted therapy for this disease (eg, NCT01643850, ClinicalTrials. gov), [9][10][11][12] as well as in other tumors that over-express CSF1. 13 While the most common CSF1 fusion partner has been reported to be COL6A3, identified in 33% of cases, and thought to result in overexpression of full-length CSF1 via promoter swapping, 7 others have reported that the CSF1 breakpoint was downstream of exon 5, and led to the replacement (by alternate sequences) of the 3 0 untranslated region (UTR) in an otherwise intact CSF1.…”

Diffuse dermal mucinosis secondary to colony‐stimulating factor 1 receptor monoclonal antibody treatment: A novel and peculiar drug‐induced diffuse cutaneous mucinosis

“…This new class of immune‐modulatory drugs has been recently incorporated in the treatment armamentarium of advanced malignant neoplasms, but also in several inflammatory conditions in which aberrant CSF1 signaling has been proved 7 . Despite all patients receiving the combination of anti‐CSF1R and anti‐PD‐L1 mAb, we consider the CSF1 pathway blockade as the cause of the observed effects, because cutaneous mucin deposits have been observed in monkeys treated with anti‐CSF1R, 8 and conversely no cases of dermal mucinosis had been published insofar as anti‐programmed death 1 or PD‐L1 therapies 9 . Notably, one of our patients presented a distinct mild lichenoid cutaneous eruption secondary to anti‐PD‐L1 treatment, previous to cutaneous mucinosis.…”