Trastuzumab

Identification

Name
Trastuzumab
Accession Number
DB00072 / P188ANX8CK
Groups
Herceptin
Description

Produced in CHO mobile cultures, trastuzumab is a recombinant IgG1 kappa, humanized monoclonal antibody [A40276] that selectively binds with excessive affinity in a cellular-based totally assay (Kd = five nM) to the extracellular domain of the human epidermal growth issue receptor protein (HER2) [FDA label]. it's miles used as a remedy of human epidermal increase factor receptor (HER)-2+ metastatic breast cancer, wherein there is a verified amplification of the HER-2 oncogene or over-expression of the HER-2 protein in tumours. it's far counseled that the overexpression or gene amplification of HER2 has been determined in about 20–30% of breast cancers and improved activation of HER2 triggers multiple downstream pathways leading to ordinary proliferation of cancer cells [A121]. Trastuzumab binds to HER2 and suppresses most cancers cells growth, proliferation, and survival without delay and in a roundabout way [A121]. In December 2017, FDA permitted Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of sufferers with breast or metastatic stomach most cancers (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). It presentations biosimilar residences as Herceptin according to clinical statistics. while Ogivri is the first biosimilar authorized within the U.S. for the remedy of breast most cancers or stomach most cancers, it's miles the second one biosimilar permitted inside the U.S. for the remedy of most cancers. Herzuma (trastuzumab-pkrb) is a biosimilar drug accepted in December 2018 for the treatment of HER2-overexpressing breast cancer.

Pharmacology

Pharmacodynamics

Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers [A40277] thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both _in vitro_ assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells _in vivo_ [A121]. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules [A40276]. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration [FDA Label].

Indication

Indicated for treatment of early stage HER2-positive breast cancer, or metastatic breast cancer that substantially overexpress HER2.

Action

Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers [A121]. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains [A121]. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression [A121]. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation [A121], and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation [A121]. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) [A40276] by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2 [A121]. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor [A40276].