Margetuximab Overview

Introduction of Margetuximab

Margetuximab (MGAH22) is a chimeric IgG monoclonal antibody (mAb) against human epidermal growth factor receptor 2 (HER2) designed for the treatment of cancer. This drug was created by Raven biotechnologies, which was later acquired by MacroGenics. Margetuximab is derived from 4D5, the parent antibody of trastuzumab. Margetuximab and trastuzumab bind the same epitope of HER2 with similar affinities and exhibit similar tumor-directed, effector cell-independent, anti-proliferative activity in breast cancer cells in vitro in the absence of immune effectors. However, five amino acid substitutions engineered into the margetuximab IgG1 Fc domain yield increased binding to both isoforms of CD16A and reduced binding to CD32B, an inhibitory FcγRIIB (CD16B), compared with trastuzumab. It is currently in phase 3 clinical trials for combination therapy in metastatic breast cancer in collaboration with Merck. Phase II trials are also in progress for gastric cancer and esophageal cancer.

Mechanism of Action of Margetuximab

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. It is important in tumorigenesis, tumor aggressiveness, and outcome in approximately one-fifth of breast and gastric cancers. Signaling pathways activated by HER2 include: mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K/Akt), phospholipase C γ, protein kinase C (PKC), and signal transducer and activator of transcription (STAT). Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. Standard care for HER2-positive malignancies includes treatment with anti-HER2 therapies, primarily trastuzumab, which has improved outcomes for patients with metastatic and early stage HER2-positive breast and advanced gastroesophageal cancers. In addition to blocking HER2, trastuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC), a potentially important mechanism for clinical efficacy. The CD16A FcγRIIIA stimulatory receptors on natural killer (NK) cells and macrophages are important for mediating ADCC. Margetuximab is derived from the parent antibody of trastuzumab. Five amino acid substitutions engineered into the margetuximab IgG1 Fc domain yield increased binding to both isoforms of CD16A and reduced binding to CD32B. In ADCC assays using effector cells from donors heterozygous or homozygous for the loweraffinity 158F variant of CD16A, margetuximab had greater potency and maximum cytotoxicity than a trastuzumab surrogate with a wild-type Fc domain. In similar assays using effector cells from donors homozygous for the higher-affinity 158V isoform of CD16A, margetuximab produced similar maximum cytotoxicity but lower EC50 than the trastuzumab surrogate. In transgenic mice expressing the human CD16A 158F/F lower affinity FcγR, margetuximab produced superior tumor growth suppression of JIMT-1 cells, a cell line insensitive to growth inhibition by anti-HER2 antibodies, compared with the trastuzumab surrogate.

Fig.1 Mechanism of action of margetuximab

Table 1. Clinical Projects of Margetuximab*

What We Provide

Therapeutic Antibody

Margetuximab

We provide high-quality Margetuximab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Reference
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Margetuximab

For research use only. Not intended for any clinical use.