Home PipelineMargetuximab (anti-HER2)


Margetuximab is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2. HER2 is expressed by tumor cells in breast, gastroesophageal, bladder and other forms of solid tumor cancers, making it a key marker for biologic therapy. Margetuximab is currently being studied as a potential treatment for metastatic breast cancer and gastroesophageal cancer.

Phase 3 Clinical Development in Metastatic Breast Cancer

During the third quarter of 2015, we initiated SOPHIA, a Phase 3 potential registration clinical trial of margetuximab in patients with metastatic breast cancer. This randomized, open-label, two-arm, interventional study will evaluate margetuximab plus chemotherapy against trastuzumab plus chemotherapy in third-line metastatic breast cancer patients with HER2 expression at the 3+ level by immunohistochemistry (IHC) or 2+ level by IHC with gene amplification. The purpose of the study is to determine whether patients treated with margetuximab plus chemotherapy have longer progression-free and overall survival than patients treated with trastuzumab plus chemotherapy. MacroGenics plans to enroll 530 patients in this study. (Learn More: SOPHIA Study Site).

Phase 1b/2 Clinical Development in Advanced Gastric Cancer

In October 2015, MacroGenics announced a collaboration with Merck to evaluate the combination of margetuximab with Merck’s anti-PD-1 therapy, pembrolizumab (KEYTRUDA®), in a Phase 1b/2 clinical trial in patients with advanced gastric cancer. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is not currently approved in gastric cancer. Treatment options for patients with advanced HER2-positive gastric cancer are extremely limited. The combination of complementary mechanisms engaged by margetuximab and pembrolizumab could provide an important alternative for patients who do not respond to currently available regimens.

The Phase 1b/2 multicenter, open-label clinical trial will be conducted in two parts. The Phase 1b portion is designed to determine the safety and tolerability of margetuximab in combination with pembrolizumab in patients with advanced gastric cancer, while the Phase 2 portion will evaluate the anti-tumor activity of margetuximab in combination with pembrolizumab in patients with advanced HER2-positive gastric cancer. MacroGenics expects to begin enrolling patients by the first quarter of 2016. (Learn More: Collaboration with Merck)

Phase 1 Study Results

Data from our Phase 1 study of margetuximab were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. Margetuximab demonstrated anti-tumor monotherapy activity across several tumor types, including patients with gastric, colorectal and head and neck cancer as well as patients with breast cancer who had received extensive prior therapy and progressed on prior HER2-directed therapy. Tumor reductions were observed in 13 of 19 evaluable patients with breast cancer, including 4 of 19 patients with confirmed partial responses. The most common adverse events (AEs) were Grade 1-2 constitutional symptoms and infusion-related reactions. These data reinforce both the safety profile of margetuximab as well as the rationale for the Phase 3 SOPHIA study. (Learn More – 2015 ASCO Poster)

Molecular Description and Mechanism of Action

Using our Fc Optimization platform, we have engineered the Fc region of margetuximab to increase its ability to mediate Fc domain-dependent activities, including enhanced tumor cell killing via antibody-dependent cell-mediated cytotoxicity, or ADCC. Specifically, we increased margetuximab’s ability to bind to activating Fc-gamma receptors and decreased 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. As a result, we believe margetuximab has 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 with Green Cross Corp. on the development and commercialization of margetuximab in South Korea. With the exception of South Korea, MacroGenics retains full worldwide rights to margetuximab.

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