Margetuximab (MGAH22) is a chimeric IgG monoclonal antibody developed for the treatments of certain types of breast and gastroesophageal cancer. The Fc-engineered platform of MacroGenics is designed that constant region (Fc region) of margetuximab can increase affinity for the CD16A polymorphism while reduce affinity for FcγRIIB (CD32B), thereby increasing antibody-dependent ADCC effect. Margetuximab is currently being investigated as a potential treatment for HER2-positive cancers types, invovlign metastatic breast cancer and advanced gastric cancer.
Margetuximab is a novel Fc-engineered humanized anti-Her2 monoclonal antibody developed to meet the needs for an agent with higher activity on Her2-positive cancers. Compared to the classical trastuzumab, the five amino acid substitutions (L235V/F243L/R292P/Y300L/P396L) are engineered into the margetuximab IgG1 Fc domain, resulting in increased binding ability to CD16A isoforms and decreased binding to CD32B (inhibitory FcγR). Margetuximab is shown to have a greater ADCC potency and maximized cytotoxicity than trastuzumab replacement in the wild-type Fc domain.
Fig.1 Fc-optimized Margetuximab.
Margetuximab is a mAb derived from 4D5, a parent antibody to trastuzumab which is already used for breast treatment. Margetuximab and trastuzumab bind to the same epitope of HER2 and share similar affinity and exhibit similar tumor orientation, exhibiting effector cell-independent and anti-tumor cell proliferation activity in breast cancer cells in vitro. Specifically, Fc-engineered margetuximab is thought to mediate its therapeutic activity against HER2-positive tumors by:
Fig.2 Mechanisms of action of Margetuximab.
Comparison between margetuximab and trastuzumab-mediated ex vivo ADCC activity against HER2-expressing breast cancer cells, using patient peripheral blood mononuclear cells (PBMC) as effector cells.
MGAH22 exhibits extremely similar binding activity compared to RES120 or trastuzumab.
MGAH22 shows increased antitumor activity in transgenic human CD16A-158F mice.
NCT ID | Status | Conditions | Lead Sponsor | Phase | Update Time |
NCT02492711 | Active, not recruiting |
HER-2 Positive Breast Cancer Metastatic Neoplasm |
MacroGenics | Phase 3 | June 4, 2019 |
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References
Creative Biolabs provides luciferase-based ADCC assay. This Jurkat cell based assay is pioneered by Creative Biolabs, and the methodology is very well accepted by the field. See attached ADCC Reporter Assay Protocol for further details.
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