Trastuzumab 126mg/250ml in Sodium chloride 0.9% infusion bags

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]. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC),[A201902] one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with [pertuzumab], which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction.[A201896]

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].