The most potent dimer for activating signalling pathways is HER2/HER3.The epitope for pertuzumab is the domain of HER2 where it binds to HER3, and pertuzumab prevents the HER2/HER3 dimer from forming, which blocks signalling by the dimer. Trastuzumab is another monoclonal antibody against HER2; its epitope is the domain where HER2 binds to another HER2 protein. The two mAbs together prevent HER2 from functioning. Chemistry and manufacturing
Pertuzumab is an immunoglobulin G1 with a variable region against the human HER2 protein, a human-mouse monoclonal 2C4 heavy chain, disulfide bound with a human-mouse monoclonal 2C4 κ-chain.It is manufactured recombinantly in CHO cells. History
The monoclonal antibody 2C4 appears to have first been published in 1990 by scientists from Genentech, the same year that F. Hoffmann-La Roche AG acquired a majority stake in Genentech.By 2003, Genentech understood that 2C4 prevented HER2 dimerizing with other HER receptors and had begun Phase I trials, aiming for a broad range of cancers, not just ones overexpressing HER2. It was the first known HER dimerization inhibitor.In 2005, Genentech presented poor results of Phase II trials of pertuzumab as a single agent in prostate, breast, and ovarian cancers, and said that it intended to continue developing it in combination with other drugs for ovarian cancer.In 2007, Genentech dropped the trade name Omnitarg.In March 2009, Roche acquired Genentech.In 2012, the results were published of the CLEOPATRA trial, a randomized placebo-controlled Phase III trial of pertuzumab in combination with trastuzumab and docetaxel in HER2-positive metastatic breast cancer.
It is also used in the same combination as a neoadjuvant (given to reduce the size of a tumor, prior to surgery or radiation) for HER2-positive early breast cancer; as of 2016 this use had not been shown to increase survival.As of 2016, pertuzumab has not been studied in people with a left ventricular ejection fraction value of ≤ 50% normal, a prior history of congestive heart failure, or conditions that could impair left ventricular function like uncontrolled hypertension, recent heart attacks, or serious cardiac arrhythmia. Caution should be used combining pertuzumab with an anthracycline. There is also no safety data available for use of pertuzumab in combination with doxorubicin.Women of child-bearing age should use contraception while taking pertuzumab; it may damage the fetus in pregnant women, and it may be secreted in breast milk. Adverse effects
In clinical trials of the three-agent combination therapy in metastatic breast cancer, adverse effects occurring in more than half the people taking it included diarrhea, hair loss, and loss of neutrophils; more than 10% of people experienced loss of neutrophils with fever, and loss of leukocytes.