Identification

Summary

Margetuximab is an Fc-engineered human/mouse chimeric IgG1κ anti-HER2 monoclonal antibody indicated for patients with HER2-positive metastatic breast cancer.

Brand Names
Margenza
Generic Name
Margetuximab
DrugBank Accession Number
DB14967
Background

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.1 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.2

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.1,2,3,4,5 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.1,2,3,4,5

Margextuximab was granted FDA approval on December 16, 2020, and is currently marketed under the trademark MARGENZA™ by MacroGenics, Inc.5

Type
Biotech
Groups
Approved, Investigational
Synonyms
  • Margetuximab
  • margetuximab-cmkb
External IDs
  • MGAH-22
  • MGAH22

Pharmacology

Indication

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.5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Margetuximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against the extracellular domain of the human epidermal growth factor receptor 2 (HER2) cell-surface protein. Also, margetuximab has an engineered Fc region that alters its affinity for the CD16A and CD32B effector cell receptors resulting in increased antibody-dependent cell-mediated cytotoxicity (ADCC). To date, the exposure-response and time course pharmacodynamic relationships of margetuximab remain incompletely characterized. Although generally well-tolerated, margetuximab carries a risk of infusion-related reactions, including symptoms such as fever, fatigue, nausea, vomiting, headache, tachycardia, hypotension, and cutaneous manifestations such as a rash or urticaria; infusion reactions may require alterations to the infusion or, in serious reactions, discontinuation.5

Mechanism of action

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.1 HER2 is an oncoprotein whose overexpression is observed in breast, gastric, and other cancers.1,2 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.1

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.1

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).1,2,3 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.1,2,3 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.2,4,5 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).2,5 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.2,3

TargetActionsOrganism
AReceptor tyrosine-protein kinase erbB-2
antagonist
Humans
Absorption

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.5

Volume of distribution

Margetuximab has a geometric mean (%CV) volume of distribution of 5.47 (22%) L.5

Protein binding

Not Available

Metabolism

Like other monoclonal antibodies, margetuximab is expected to be metabolized into smaller peptides through various proteases and catabolic pathways.5

Route of elimination

Not Available

Half-life

Margetuximab has a geometric mean (%CV) terminal half-life of 19.2 (28%) days.5

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.5

Adverse Effects
Adverseeffects
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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.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Margetuximab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Margetuximab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Margetuximab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Margetuximab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Margetuximab.
AmivantamabThe risk or severity of adverse effects can be increased when Margetuximab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Margetuximab.
AnsuvimabThe risk or severity of adverse effects can be increased when Margetuximab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Margetuximab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Margetuximab.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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International/Other Brands
Margenza (MacroGenics, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MargenzaInjection, solution, concentrate25 mg/1mLIntravenousMacroGenics, Inc2021-01-15Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
K911R84KEW
CAS number
1350624-75-7

References

Synthesis Reference

Nordstrom JL, Gorlatov S, Zhang W, Yang Y, Huang L, Burke S, Li H, Ciccarone V, Zhang T, Stavenhagen J, Koenig S, Stewart SJ, Moore PA, Johnson S, Bonvini E: Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcgamma receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi: 10.1186/bcr3069.

General References
  1. Kreutzfeldt J, Rozeboom B, Dey N, De P: The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res. 2020 Apr 1;10(4):1045-1067. eCollection 2020. [Article]
  2. Nordstrom JL, Gorlatov S, Zhang W, Yang Y, Huang L, Burke S, Li H, Ciccarone V, Zhang T, Stavenhagen J, Koenig S, Stewart SJ, Moore PA, Johnson S, Bonvini E: Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcgamma receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi: 10.1186/bcr3069. Epub 2011 Nov 30. [Article]
  3. Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nordstrom JL, Li H, Chichili GR, Moore PA, Hong S, Stewart SJ, Baughman JE, Lechleider RJ, Burris HA: First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017 Apr 1;28(4):855-861. doi: 10.1093/annonc/mdx002. [Article]
  4. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  5. FDA Approved Drug Products: MARGENZA (margetuximab) injection [Link]
RxNav
2473850
Wikipedia
Margetuximab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentHER2/Neu-positive Breast Cancer / Neoplasms, Metastatic1
2CompletedTreatmentBreast Cancer1
2RecruitingTreatmentBreast Cancer / Breast Cancer, Stage II / Breast Cancer, Stage III / HER2/Neu-positive Breast Cancer1
2RecruitingTreatmentMetastatic Breast Cancer1
2, 3RecruitingTreatmentGastro Esophageal Junction Cancer / Her-2 Positive Gastric Cancer / Malignant Neoplasm of Stomach1
1Active Not RecruitingTreatmentBreast Cancer (Triple Negative Breast Cancer (TNBC)) / Cervical Cancers / Cholangiocarcinomas / HER2/Neu-positive Breast Cancer / Neoplasms, Hematologic / Non-Small Cell Lung Carcinoma (NSCLC) / Ovarian Cancer / Small Cell Lung Cancer (SCLC) / Solid Tumors, Advanced Solid Tumors / Squamous Neck Carcinoma of the Head and Neck Cancer (SCCHN)1
1Active Not RecruitingTreatmentBreast Cancer / Malignant Neoplasm of Stomach1
1CompletedTreatmentMetastatic Breast Cancer With HER2 Positive1
1, 2CompletedTreatmentEsophageal Neoplasms Malignant / Malignant Neoplasm of Stomach1
Not AvailableApproved for MarketingNot AvailableHER2-positive Carcinoma / HER2/Neu-positive Breast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous25 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Curator comments
Margetuximab exhibited a HER2-binding EC50 (95% CI) of 39.33 (29.45 - 52.52) ng/mL in an antigen-capture enzyme-linked immunosorbent assay. HER2 binding is the main mediator of margetuximab efficacy.
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. FDA Approved Drug Products: MARGENZA (margetuximab) injection [Link]

Drug created at May 20, 2019 14:38 / Updated at July 28, 2021 15:00