| Candidate ID: | R1549 |
| Source ID: | DB14967 |
| Source Type: | approved; investigational |
| Compound Type: |
biotech
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| Compound Name: |
Margetuximab
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| Synonyms: |
Margetuximab; margetuximab-cmkb
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| Molecular Formula: |
--
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| SMILES: |
--
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| DrugBank Description: |
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 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 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 . 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 .
Margextuximab was granted FDA approval on December 16, 2020, and is currently marketed under the trademark MARGENZA™ by MacroGenics, Inc.
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| CAS Number: |
1350624-75-7
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| Molecular Weight: |
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| DrugBank 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.
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| DrugBank Pharmacology: |
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.
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| DrugBank MoA: |
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 , a monoclonal antibody (mAb) that binds the HER2 extracellular domain. works through several mechanisms: binding induces receptor internalization and c-CBL-mediated HER2 degradation; effector cell binding to the Fc region of through CD16A results in antibody-mediated cell-dependent cytotoxicity (ADCC); finally, binding dampens HER2 activation, phosphorylation, and subsequent downstream oncogenic signalling.
Despite demonstrated clinical efficacy, 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 . Margetuximab is derived from the same mouse 4D5 clone as , 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 (K<sub>D</sub> of 89 nM vs 415 nM) and low affinity (K<sub>D</sub> of 161 nM vs 1059 nM) CD16A receptors and decreased binding to the inhibitory CD32B receptor (K<sub>D</sub> 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.
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| Targets: |
Receptor tyrosine-protein kinase erbB-2 antagonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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