First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors

Abstract

Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820. Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal. Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%). AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. .

HLA class II expression on tumor cells and low numbers of tumor‐associated macrophages predict clinical outcome in oropharyngeal cancer

“…Indeed, we showed that both high HLA‐DP/DQ/DR expression and low numbers of TAMs are required to observe a beneficial effect in survival, as equal expression of both markers did not significantly affect DFS or DSS. Also, infiltration of TAMs are known to affect treatment responses in several tumor types and preclinical and clinical studies using anti‐CSFR1 Ab (macrophage colony‐stimulating factor receptor 1) have been performed . We, therefore, speculate that immunotherapy treatment targeting TAMs might be beneficial especially for patients with high expression of HLA‐DP/DQ/DR on tumor cells.…”

“…Also, infiltration of TAMs are known to affect treatment responses in several tumor types 45 and preclinical and clinical studies using anti-CSFR1 Ab (macrophage colony-stimulating factor receptor 1) have been performed. [46][47][48] We, therefore, speculate that immunotherapy treatment targeting TAMs might be beneficial especially for patients with high expression of HLA-DP/DQ/ DR on tumor cells.…”

Inhibition of BACE1 Facilitates Macrophage-based Immunotherapy to Suppress Malignant Growth of Glioblastoma

“…Targeting or reeducating TAMs by inhibiting colony-stimulating factor 1 receptor (CSF-1R) showed suppression of GBM growth in mouse models 42 , but clinical trials with CSF-1R inhibitors failed to show signi cant e cacy for GBM patients 58 . Because CSF-1R is also expressed on circulating monocytes and other normal cells, targeting it resulted in serious toxic effects in the clinical trials 59 , making therapeutics targeting CSF-1R ineffective for clinical use 58,60 .…”

Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer

“…More recently, the evaluation of the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a fully human antibody against CSF1R (AMG 820) in a first-in-humans phase-I study for advanced solid tumors was published [ 62 ]. This study demonstrated that the anti-CSF1R antibody AMG 820 was tolerated with manageable toxicity up to 20 mg/kg every two weeks.…”