Margetuximab
目录号 : GC68304Margetuximab (MGAH22) 是一种嵌合抗 HER2 单克隆抗体，具有优化的 Fc 结构域，EC50 为 39.33 ng/mL。Margetuximab 可用于转移性 HER2 阳性乳腺癌研究。
Cas No.:1350624-75-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Datasheet
Margetuximab (MGAH22) is a chimeric anti-HER2 monoclonal antibody optimized Fc domain, with an EC50 value of 39.33 ng/mL. Margetuximab can be used for researching metastatic HER2-positive breast cancer[1].
Margetuximab (MGAH22) enhances the antibody-dependent cell-mediated cytotoxicity activity of effector cells expressing the CD16A-158F variant[1].
Cell Proliferation Assay
| Cell Line: | JIMT-1, MCF-7, ZR-75-1, SKBR-3, HT-29, SW750 and N87[1] |
| Concentration: | 0.001-1000 ng/mL |
| Incubation Time: | 6 days |
| Result: | Enhances the antibody-dependent cell-mediated cytotoxicity activity of effector cells expressing the CD16A-158F variant. |
Margetuximab (2-4 mg/kg; IP 5 or 6 times at weekly) can firstly and significantly reduces the tumor size at day 30 - 37 in mice model[1].
Margetuximab (15-150 mg/kg; IV; 6 weekly) exhibits well tolerated in cynomolgus monkeys, decreases NK cells by an average of 51%, and induces IL-6 release[1].
Margetuximab (50 mg/kg; IV; single dosage) exhibits favorable safety profile[1].
Pharmacokinetic Parameters of Margetuximab in cynomolgus monkeys[1].
| Male, IV (50 mg/kg) | Female, IV (50 mg/kg) | |
| Cmax (mg/mL) | 1.62 ± 0.10 | 1.70 ± 0.14 |
| AUC0-¥ (mg.hour/mL) | 294.1 ± 53.2 | 314.2 ± 31.3 |
| T1/2β (days) | 9.3 ± 1.8 | 9.7 ± 1.1 |
| Clearance (mL/hour) | 0.43 ± 0.07 | 0.40 ± 0.04 |
| VSS (mL) | 132 ± 2 | 127 ± 8 |
[1]. Nordstrom JL, et al. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi:10.1186/bcr3069
| Cas No. | 1350624-75-7 | SDF | Download SDF |
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial
JAMA Oncol 2021 Apr 1;7(4):573-584.PMID:33480963DOI:10.1001/jamaoncol.2020.7932.
Importance: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody Margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective: To compare the clinical efficacy of Margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, setting, and participants: The SOPHIA phase 3 randomized open-label trial of Margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions: Investigators selected chemotherapy before 1:1 randomization to Margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main outcomes and measures: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results: A total of 536 patients were randomized to receive Margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the Margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with Margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring Margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with Margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. Conclusions and relevance: In this phase 3 randomized clinical trial, Margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. Trial registration: ClinicalTrials.gov Identifier: NCT02492711.
Margetuximab: First Approval
Drugs 2021 Apr;81(5):599-604.PMID:33761116DOI:10.1007/s40265-021-01485-2.
The second-generation anti-human epidermal growth factor receptor2 protein (HER2) monoclonal antibody Margetuximab (MARGENZA™, margetuximab-cmkb) is being developed for the treatment of HER2-positive breast cancer, gastric cancer and gastro-oesophageal junction cancer. The antibody has been engineered for increased binding to activating Fcγ receptor IIIA (CD16A) and decreased binding to inhibitory Fcγ receptor IIB (CD32B) relative to trastuzumab with the aim of improving response rates. Based on the results of the phase III SOPHIA trial Margetuximab has been approved in the USA for use in combination with chemotherapy as treatment of previously-treated metastatic HER2-positive breast cancer. This article summarizes the milestones in the development of Margetuximab leading to this first approval.
MAHOGANY: Margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma
Future Oncol 2021 Apr;17(10):1155-1164.PMID:33263418DOI:10.2217/fon-2020-1007.
Standard-of-care, first-line therapy for patients with advanced HER2+ gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2. Margetuximab is an Fc-optimized mAb that binds HER2. Retifanlimab, a humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. Tebotelimab, an IgG4κ bispecific DART® molecule, binds PD-1 and lymphocyte activation gene 3 concomitantly, disrupting these nonredundant inhibitory pathways to further restore exhausted T-cell function. Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating Margetuximab plus retifanlimab with/without chemotherapy and Margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. Clinical trial registration: NCT04082364 (ClinicalTrials.gov).
Margetuximab for the treatment of HER2-positive metastatic breast cancer
Expert Opin Biol Ther 2021 Feb;21(2):127-133.PMID:33238772DOI:10.1080/14712598.2021.1856812.
Introduction: No specific standard treatment is currently recommended for HER2-positive advanced breast cancer (BC) patients progressing to dual HER2 blockade and to trastuzumab emtansine (TDM-1). However, several novel anti-HER2 agents are emerging and rapidly revolutionizing this setting. Among these, the FC-engineered monoclonal antibody Margetuximab has recently demonstrated to slightly improve progression-free survival (PFS) compared with trastuzumab, when combined with chemotherapy for pretreated HER2-positive advanced BC. Areas covered: The present review article recapitulates the clinical development of Margetuximab, critically discussing its implications in the current landscape of BC treatment algorithms. Expert opinion: The clinical role of Margetuximab can only be interpreted in view of the rapidly evolving treatment landscape for pretreated HER2-positive advanced BC. Indeed, the recently approved anti-HER2 agents tucatinib and trastuzumab deruxtecan currently represent appealing options for the post-TDM1 setting, while Margetuximab may have a role after progression to the abovementioned agents, in case of a future approval. Regardless of its clinical uptake, it should be noted that the development of Margetuximab has relevantly improved our biological understanding of HER2-positive BC, highlighting the implication of patient's genotype in determining treatment outcomes, as well as the relevance of antibody-dependent cellular cytotoxicity (ADCC) in the context of HER2-blockade.
Margetuximab and trastuzumab deruxtecan: New generation of anti-HER2 immunotherapeutic agents for breast cancer
Mol Immunol 2022 Dec;152:45-54.PMID:36272249DOI:10.1016/j.molimm.2022.10.005.
Advances in the development of anti-HER2 monoclonal antibodies (mAbs) represent one of the most significant milestones in the treatment of HER2+ breast cancer patients. However, HER2+ metastatic breast cancer (MBC) patients display resistance towards first-generation anti-HER2 mAbs or antibody-drug conjugate (ADC) treatment. In recent years, new generation of anti-HER2 mAb and ADC including Margetuximab and trastuzumab deruxtecan (T-DXd), respectively, have been approved for the treatment of previously treated HER2+ MBC patients. The successes of Margetuximab and T-DXd have renewed the interest in the research and development of anti-HER2 immunotherapies for both HER2+ and HER2-low breast cancer patients. In this review, we focus on these two immunotherapeutics in terms of their mechanisms of action, preclinical findings and clinical trials leading to their approval, as well as the mechanisms of resistance to conventional anti-HER2 immunotherapies (i.e. trastuzumab, pertuzumab and T-DM1). In the future, combination of either Margetuximab or T-DXd with small molecule inhibitors such as tyrosine kinase inhibitors that elicit anticancer immunogenicity may further enhance the efficacy of Margetuximab or T-DXd in the treatment of HER2+ MBC patients.