The structure of HER2 and pertuzumab
|Source||Humanized (from mouse)|
|Trade names||Perjeta; Omnitarg|
|Licence data||US FDA:|
|CAS Registry Number|
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Pertuzumab (also called 2C4, trade name Perjeta) is a monoclonal antibody marketed by Genentech for the treatment of HER2-positive breast cancer, in combination with trastuzumab and docetaxel. The first of its class in a line of agents called "HER dimerization inhibitors". By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth. Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer on June 8, 2012. Pertuzumab was developed at Genentech and is now owned by Roche which acquired Genentech in 2009.
Mechanism of Action
The HER2 pathway is an important target for breast cancer therapy because it stimulates cell proliferation and cell growth; therefore, if overexpressed it can cause uncontrollable growth. HER2 positive breast cancer is caused by a gene mutation that results in an overexpression of the receptor on the cell membrane that has an intracellular domain with tyrosine kinase activity in approximately 20% of breast cancer tumors. HER2 receptors are ligand-independent; therefore, they are always in an active conformation and can either homodimerize with another HER2 receptor or heterodimerize with a different receptor of the HER family in order to activate certain downstream signaling pathways through phosphorylation of the tyrosine kinases. When phosphorylated, HER2 sends a signal from its intracellular domain that activates several biochemical pathways such as the MAPK pathway, the PI3K pathway, and the PKB pathway which all play a part in cancer progression, and it deactivates other processes necessary for controlled division such as apoptosis. During cell division there are check points that help avoid uncontrolled proliferation; however, the overexpression of HER2 is able to bypass the checkpoints through the upregulation of mitotic factors that control checkpoint assembly and disrupts the cell cycle which promotes constant cell growth and survival resulting in tumor formation. These activated pathways also stimulate angiogenesis which helps sustain the constant proliferation.
Pertuzumab is well tolerated with very low toxicity levels; therefore it is commonly used in conjunction with Trastuzumab – a monoclonal antibody that targets the subdomain IV of HER2 – due to the development of primary and acquired resistance in the majority of patients since Trastuzumab is only able to block the homodimerization of HER2. As resistance to Trastuzumab develops there is an upregulation of other members of the HER family in order to compensate for the lack of HER2 ligand-independent signaling. On the other hand, Pertuzumab binds to the dimerization domain of HER2; therefore, blocking the ability of HER2 to heterodimerize with other members of the HER family and initiate HER2 ligand-dependent signaling. The HER2/HER3 dimer is thought to be the most potent in terms of the interaction strength and the amplification of downstream signaling. Experiments done in vitro show correlations between reduced HER3 and reduced cell proliferation suggesting that HER3 has a high affinity for HER2 heterodimerization, and that this heterodimerization plays an important role in the signal transduction process even though HER3 has no known kinase embedded in its structure. In this way, Pertuzumab works well as a dual inhibitor with other treatments such as Trastuzumab.
As with any antibody, a mechanism of action for Pertuzumab is thought to be through triggering an immune response to destroy the cell when it binds to the extracellular domain of HER2; this is known as antibody dependent cellular cytotoxicity.
Early clinical trials of pertuzumab in prostate, breast, and ovarian cancers met with limited success.
The dosage of pertuzumab used in the pivotal phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial was as follows: IV 840 mg loading dose followed by IV 420 mg every three weeks.
The pharmacokinetics of intravenous pertuzumab appear to be unaffected by age and no drug-drug interaction has been reported with docetaxel. The pharmacokinetics and pharmacodynamics of pertuzumab were summarized in a Feb 2012 review by Gillian Keating.
The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects in the randomized, double-blind, multinational, phase III CLEOPATRA trial.
Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breast cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).
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