Home PipelineMargetuximab (anti-HER2)

Background

Margetuximab is an investigational monoclonal antibody that targets HER2-expressing tumors, including certain types of breast and gastroesophageal cancers. HER2 is critical for the growth of many types of tumors. Using MacroGenics’ Fc Optimization platform, the constant region (Fc region) of margetuximab was engineered to increase its ability to kill tumor cells through an Fc-dependent mechanism, including antibody dependent cell-mediated cytotoxicity (ADCC). Margetuximab is currently being studied as a potential treatment for HER2-positive metastatic breast cancer and advanced gastric cancer.

Phase 3 Clinical Development in HER2+ Metastatic Breast Cancer

Margetuximab is being evaluated in SOPHIA, a Phase 3 clinical trial of margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer. Results from the SOPHIA study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2019 and at the San Antonio Breast Cancer Symposium (SABCS) in December 2019.

The U.S. FDA has granted Fast Track designation for the investigation of margetuximab for treatment of patients with metastatic or locally advanced HER2 positive breast cancer who have previously been treated with anti-HER2-targeted therapy.

Phase 2/3 Clinical Development in Advanced Gastric Cancer

Margetuximab is being evaluated in a Phase 2 clinical trial in patients with HER2-positive gastric or gastroesophageal junction cancer in combination with an anti-PD-1 monoclonal antibody. Enrolled patients had relapsed or refractory advanced HER2-positive gastric or gastroesophageal junction cancer with disease progression after or resistance to treatment with trastuzumab plus chemotherapy. Recent data  from this study were presented at the annual meeting of the European Society for Medical Oncology (ESMO) in September 2019.

In addition, a registration-directed Phase 2/3 MAHOGANY study of margetuximab plus a checkpoint inhibitor with or without chemotherapy in front-line patients has recently opened to patient enrollment.

Molecular Description and Mechanism of Action

Using MacroGenics’ Fc Optimization platform, the constant region (Fc region) of margetuximab was engineered to increase its ability to kill tumor cells through an Fc-dependent mechanism, including ADCC. Specifically, margetuximab’s ability to bind to activating Fc-gamma receptors was increased and its ability to bind to the Fc-gamma inhibitory receptor on immune effector cells, including monocytes, macrophages, dendritic cells and natural killer, or NK, cells, was decreased. As a result, margetuximab may have the potential to be effective in a broader population than is currently treated with trastuzumab and may overcome resistance in populations that no longer respond to trastuzumab. (Learn More: Fc Optimization Platform)

Margetuximab is believed to mediate its therapeutic activity against HER2+ tumors by a combination of mechanisms including:

  • Modulation of HER2 signaling, resulting in growth retardation or the induction of apoptosis, or cell death;
  • ADCC and improved binding to immune cells to enhance destruction of HER2+ tumor cells; and
  • Presentation of tumor antigens by cells such as macrophages that take up and display the antigens to other cells of the immune system, including T cells.

Our Rights

MacroGenics is collaborating on the development and commercialization of margetuximab with Green Cross Corp. in South Korea and Zai Lab in Greater China. MacroGenics retains full development and commercialization rights in all other territories.

Clinical Trials

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