Emactuzumab
(Synonyms: RG 7155; RO 5509554) 目录号 : GC66380
Emactuzumab (RG 7155) 是一种特异性单克隆抗体，可抑制集落刺激因子 1 受体 (CSF1R) 的激活。Emactuzumab 对 CSF-1R 具有高亲和力，Ki 值为 0.2 nM，可阻断 CSF-1R 二聚化。Emactuzumab 可用于多种疾病的研究，如弥漫型腱鞘巨细胞瘤（dt-GCT）。
Cas No.:1448221-67-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
IC50: 0.2 nM (CSF-1R)[2]
Emactuzumab(RG 7155) is a specific monoclonal antibody that inhibits colonystimulating factor 1 receptor (CSF1R) activation. Emactuzumab has high affinity for CSF-1R with Ki value of 0.2 nM to blocks CSF-1R dimerization. Emactuzumab can be used for the research of several diseases, such as diffuse-type tenosynovial giant cell tumour (dt-GCT) [1][2].
Emactuzumab (RG 7155) binds to human and cynomolgus CSF-1R with high affinity (Kd = 0.2 nM) to blocks CSF-1R dimerization[2].
RG7155 (0-10 μg/mL, 7 days) potently inhibited the viability of CSF-1-differentiated macrophages with an IC50 of 0.3 nM by inducing cell death[2].
RG7155 (30 μg/mL, 6 days) induces cell death of in vitro-differentiated human M2-like macrophages[2].
Cell Viability Assay[2]
| Cell Line: | CSF-1 and/or GM-CSF Macrophages |
| Concentration: | 0-10 μg/mL |
| Incubation Time: | 7 days |
| Result: | Resulted cell death of CSF-1-differentiated macrophages. |
Emactuzumab(RG 7155) (i.v.; 0.1、1、10、30 and 100 mg/kg; once) increases CSF-1 concentration in nonhuman primates' peripheral blood[2].
RG7155 (i.v.; 0, 30, and 100 mg/kg; once weekly; for 2 weeks) depletes CSF-1R+CD163+ macrophages in vivo[2].
| Animal Model: | cynomolgus monkeys Macaca fascicularis[2] |
| Dosage: | 0.1, 1, 10, 30 and 100 mg/kg (male cynomolgus monkeys) 0, 30, and 100 mg/kg (male and female cynomolgus) |
| Administration: | i.v., once (male cynomolgus monkeys) i.v., once weekly, for 2 weeks(male and female cynomolgus) |
| Result: | Increased CSF-1 concentration in serum. Efficiently reduced CSF-1R and CD68+163+ macrophages in the liver (Kupffer cells) and colon of cynomologus monkeys. |
| Cas No. | 1448221-67-7 | SDF | Download SDF |
| 别名 | RG 7155; RO 5509554 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Anti-CSF-1R Emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
J Immunother Cancer 2022 May;10(5):e004076.PMID:35577503DOI:10.1136/jitc-2021-004076.
Background: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) Emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). Methods: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of Emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. Results: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of Emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. Conclusion: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
Treatment updates on tenosynovial giant cell tumor
Curr Opin Oncol 2022 Jul 1;34(4):322-327.PMID:35837703DOI:10.1097/CCO.0000000000000853.
Purpose of review: Diffuse-type tenosynovial giant cell tumor (dt-TGCT) is a benign clonal neoplastic proliferation arising from the synovium. Patients are often symptomatic, require multiple surgical procedures during their lifetime, and have reduced quality of life (QoL). Surgery is the main treatment with relapse rates ranging from 14 to 55%. The treatment strategy for patients with dt-TGCT is evolving. The purpose of this review is to describe current treatment options, and to highlight recent developments in the knowledge of the molecular pathogenesis of dt-TGCT as well as related therapeutic implications. Recent findings: TGCT cells overexpress colony-stimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumor, has led to clinical trials with CSF1R inhibitors. These inhibitors include small molecules such as pexidatinib, imatinib, nilotinib, DCC-3014 (vimseltinib), and the monoclonal antibody RG7155 (Emactuzumab). Summary: In conclusion, D-TGCT impairs patients' QoL. The evidence that the pathogenetic loop of D-TGCT can be inhibited has changed the therapeutic armamentarium for this condition. Clinical trials of agents that target CSF1R are currently ongoing. All this new evidence should be taken into consideration within multidisciplinary management.
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment
Mol Cancer Ther 2016 Dec;15(12):3077-3086.PMID:27582524DOI:10.1158/1535-7163.MCT-16-0157.
Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor-induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R-blocking antibody RG7155 (Emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R-targeting agents. Mol Cancer Ther; 15(12); 3077-86. ©2016 AACR.
Phase I study of Emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages
Ann Oncol 2019 Aug 1;30(8):1381-1392.PMID:31114846DOI:10.1093/annonc/mdz163.
Background: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of Emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. Patients and methods: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (Emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. Results: No maximum tolerated dose was reached in either study arm, and the safety profile of Emactuzumab alone and in combination does not appear to preclude its use. No patients receiving Emactuzumab monotherapy showed an objective response; the objective response rate for Emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. Conclusions: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).
PK/PD Mediated Dose Optimization of Emactuzumab, a CSF1R Inhibitor, in Patients With Advanced Solid Tumors and Diffuse-Type Tenosynovial Giant Cell Tumor
Clin Pharmacol Ther 2020 Sep;108(3):616-624.PMID:32575160DOI:10.1002/cpt.1964.
Targeted biological therapies may achieve maximal therapeutic efficacy at doses below the maximum tolerated dose (MTD); therefore, the search for the MTD in clinical studies may not be ideal for these agents. Emactuzumab is an investigational monoclonal antibody that binds to and inhibits the activation of the cell surface colony-stimulating factor-1 receptor. Here, we show how modeling target-mediated drug disposition coupled with pharmacodynamic end points was used to optimize the dose of Emactuzumab without defining an MTD. The model could be used to recommend doses across different disease indications. The approach recommended an optimal biological dose of Emactuzumab for dosing every 2 weeks (q2w) ≥ 900 mg, approximately three-fold lower than the highest dose tested clinically. The model predicted that Emactuzumab doses ≥ 900 mg q2w would achieve target saturation in excess of 90% over the entire dosing cycle. Subsequently, a dose of 1,000 mg q2w was used in the extension phase of a phase I study of Emactuzumab in patients with advanced solid tumors or diffuse-type tenosynovial giant cell tumor. Clinical data from this study were consistent with model predictions. The model was also used to predict the optimum dose of Emactuzumab for use with dosing every 3 weeks, enabling dosing flexibility with respect to comedications. In summary, this work demonstrates the value of quantitative clinical pharmacology approaches to dose selection in oncology as opposed to traditional MTD methods.