Margetuximab

Overview

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.

ADCC Enhancement Technology for Margetuximab

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.

Fc-optimized Margetuximab. Fig.1 Fc-optimized Margetuximab.

Mechanism of Action of 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:

Mechanisms of action of Margetuximab. Fig.2 Mechanisms of action of Margetuximab.

ADCC Activity

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.

Margetuximab

Antigen Binding Characterization

MGAH22 exhibits extremely similar binding activity compared to RES120 or trastuzumab.

Margetuximab

Anti-tumor Efficacy in Preclinical

MGAH22 shows increased antitumor activity in transgenic human CD16A-158F mice.

Margetuximab

Clinical Trial Data for Margetuximab

Margetuximab

Margetuximab

Clinical Development Status

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

  1. T Bang YJ.; et al. First-in-human Phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Annals of Oncology. 2017:mdx002.
  2. 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 Research.13,6(2011-11-30), 2011, 13(6).

RESOURCES

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. 

All products and services are for Research Use Only. Do Not use in humans.

CASE STUDY

ADCC Assay WT vs AfucoTM Mabs  Visit

Resource

Antibody Fc Engineering: Towards Better Therapeutics  Visit

ONLINE INQUIRY

Creative Biolabs has established a team of customer support scientists ready to discuss ADCC/CDC optimization strategies, antibody production, bioinformatics analysis and other molecular biology/biotechnology issues.

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