Margetuximab
Margetuximab Uses, Dosage, Side Effects, Food Interaction and all others data.
The HER2 oncoprotein, the product of the human ERBB2/mouse neu genes, is a member of the HER family of receptor tyrosine kinases that includes the epidermal growth factor receptor (EGFR). Of the various subtypes of breast cancer, HER2-positive breast cancer is characterized by ERBB2 overexpression, a higher grade, a more aggressive phenotype, and a worse prognosis compared to HER2-negative cancer. The introduction of trastuzumab improved patient outcomes in HER2-positive breast cancer, but notably depended substantially on polymorphisms in the FcγRIIIA/CD16A receptor, whereby low affinity 158F CD16A variants are associated with shorter progression-free survival and worse patient outcomes.
Margetuximab (formerly MGAH22) is an Fc-engineered human/mouse chimeric anti-HER2 IgG1κ monoclonal antibody derived from the same mouse 4D5 clone that trastuzumab is derived from and is produced in Chinese Hamster Ovary (CHO) culture. Margetuximab binds to the same epitope on the HER2 extracellular domain and induces the same effects as trastuzumab. However, due to its modified Fc region, margetuximab binds with higher affinity to both CD16A variants and exhibits weaker binding to the inhibitory CD32B Fc receptor, resulting in more efficient antibody-dependent cell-mediated cytotoxicity (ADCC) and increased efficacy compared to trastuzumab.
Margextuximab was granted FDA approval on December 16, 2020, and is currently marketed under the trademark MARGENZA™ by MacroGenics, Inc.
| Trade Name | Margetuximab |
| Availability | Prescription only |
| Generic | Margetuximab |
| Margetuximab Other Names | Margetuximab, margetuximab-cmkb |
| Related Drugs | Arimidex, Ibrance, Femara, Xeloda, Herceptin, Lynparza |
| Weight | 25mg/ml |
| Type | Intravenous solution |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Margetuximab is an Fc-engineered human/mouse chimeric IgG1κ anti-HER2 monoclonal antibody indicated for patients with HER2-positive metastatic breast cancer.
Margetuximab is an anti-HER2 monoclonal antibody indicated, in combination with chemotherapy, for the treatment of metastatic HER2-positive breast cancer in adult patients who have received two or more prior anti-HER2 regimens with at least one prior regimen for metastatic disease.
Margetuximab is also used to associated treatment for these conditions: Metastatic Breast Cancer With HER2 Positive
How Margetuximab works
The HER family of transmembrane receptor tyrosine kinases (RTKs) includes the epidermal growth factor receptor (EGFR/HER1), HER2, HER3, and HER4 proteins; HER family members are generally involved in cell proliferation, angiogenesis, cell motility and invasiveness, and resistance to apoptosis. HER2 is an oncoprotein whose overexpression is observed in breast, gastric, and other cancers. HER2 undergoes both ligand-independent homodimerization and ligand-dependent heterodimerization with other HER family members, followed by RTK phosphorylation and induction of downstream oncogenic signalling pathways. EGFR/HER2 dimerization promotes EGFR recycling and prolonged signalling while HER2/HER3 dimerization potently stimulates the downstream PI3K/AKT pathway; HER2 homodimerization directly activates the RAS/MAPK pathway and indirectly activates the PI3K/AKT pathway.
The prototypical anti-HER2 therapy is trastuzumab, a monoclonal antibody (mAb) that binds the HER2 extracellular domain. Trastuzumab works through several mechanisms: trastuzumab binding induces receptor internalization and c-CBL-mediated HER2 degradation; effector cell binding to the Fc region of trastuzumab through CD16A results in antibody-mediated cell-dependent cytotoxicity (ADCC); finally, trastuzumab binding dampens HER2 activation, phosphorylation, and subsequent downstream oncogenic signalling.
Despite demonstrated clinical efficacy, trastuzumab efficacy is dependent on polymorphisms in CD16A. Effector cells such as natural killer (NK) cells and macrophages bind to mAbs through Fc receptors such as CD16A (FcγRIIIA), CD32A (FcγRIIA), and the inhibitory CD32B (FcγRIIB). CD16A has both high affinity (with valine at position 158; 158V) and low affinity (158F) variants; patients heterozygous or homozygous for the 158F variant have poorer responses to trastuzumab. Margetuximab is derived from the same mouse 4D5 clone as trastuzumab, but with a modified (MGFc0264) Fc region encoding five amino acid substitutions (L235V, F243L, R292P, Y300L, and P396L) to alter Fc receptor binding. Comparatively, margetuximab exhibits increased binding to both the high affinity (KD of 89 nM vs 415 nM) and low affinity (KD of 161 nM vs 1059 nM) CD16A receptors and decreased binding to the inhibitory CD32B receptor (KD of 437 nM vs 52 nM). This, in turn, increases ADCC and anti-tumour effect, especially in cells expressing lower levels of HER2 and in patients with the lower affinity 158F CD16A variant.
Toxicity
Toxicity information regarding margetuximab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as infusion-related reactions. Symptomatic and supportive measures are recommended.
Food Interaction
No interactions found.Margetuximab Hypertension interaction
[Moderate] Decreases in left ventricular ejection fraction (LVEF) have been reported with agents that block HER2 activity.
Patients who have received prior anthracyclines, those who received anthracycline after stopping therapy with agents that block HER2 activity, or patients who received prior radiotherapy to the chest area may be at higher risk of decreased LVEF.
Therapy with these agents should be administered cautiously in patients with a previous history of heart conditions.
Evaluate cardiac function before, during, and upon completion of treatment.
Withhold or discontinue therapy with agents that block HER2 activity as appropriate, and for a confirmed clinically significant decrease in left ventricular function, or if the LVEF has not improved or has declined further.
It is recommended to monitor overall cardiac function and LVEF by echocardiogram or MUGA scan as appropriate.
Margetuximab Disease Interaction
Volume of Distribution
Margetuximab has a geometric mean (%CV) volume of distribution of 5.47 (22%) L.
Elimination Route
In patients with HER2-positive relapsed or refractory breast cancer, margetuximab administered at the recommended dose results in a steady-state geometric mean (%CV) Cmax of 466 (20%) μg/mL and an AUC0-21d of 4120 (21%) μg*day/mL. After a single dose, the Cmax and AUC0-21d increase in a dose-proportional manner from 10 to 18 mg/kg, which is 0.67 to 1.2 times the recommended dose. The time to steady-state is two months at the recommended dosage, and the accumulation ratio is 1.65 based on the AUC0-21d. There are no significant effects on margetuximab exposure by altering the infusion time in the range of 30 minutes to 120 minutes.
Half Life
Margetuximab has a geometric mean (%CV) terminal half-life of 19.2 (28%) days.
Clearance
Margetuximab has a geometric mean (%CV) clearance of 0.22 (24%) L/day. Four months following margetuximab discontinuation, the concentration is approximately 3% of the steady-state trough serum concentration.
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