Pertuzumab, sold under the brand name Perjeta, is a
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
used in combination with
trastuzumab
Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wit ...
and
docetaxel
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...
for the treatment of metastatic
HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
-positive
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
; it also used in the same combination as a
neoadjuvant
Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size o ...
in early HER2-positive breast cancer.
Side effects in more than half the people taking it include diarrhea, hair loss, and
loss of neutrophils; more than 10% experience
loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes,
nail disease
A nail disease or onychosis is a disease or deformity of the nail. Although the nail is a structure produced by the skin and is a skin appendage, nail diseases have a distinct classification as they have their own signs and symptoms which may r ...
, and muscle pain.
Women who are pregnant or planning on getting pregnant should not take it, it was not studied in people with certain heart conditions and should be used in caution in such people, and it should not be used with an
anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...
.
It is unknown if pertuzumab interacts with
doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
.
It is the first-in-class of a kind of drug called a "
HER
Her is the objective and possessive form of the English-language feminine pronoun She (pronoun), she.
Her, HER or H.E.R. may also refer to:
Arts, entertainment and media Music
* H.E.R. (born 1997), American singer
**H.E.R. (album), ''H.E.R.'' ...
dimerization inhibitor" — it inhibits the
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
ization of HER2 with other HER receptors, which prevents them from
signalling
In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...
in ways that promote cell growth and proliferation.
[
It was discovered and developed by ]Genentech
Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...
and was first approved in 2012.[
]
Medical uses
Pertuzumab is administered as an intravenous infusion in combination with trastuzumab
Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wit ...
and docetaxel
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...
as a first line treatment for HER2-positive metastatic breast cancer. It is also used in the same combination as a neoadjuvant
Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size o ...
(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.
, 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
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...
function like uncontrolled hypertension, recent heart attacks, or serious cardiac arrhythmia. Caution should be used combining pertuzumab with an anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...
. There is also no safety data available for use of pertuzumab in combination with doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
.
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. After docetaxel was dropped in some people, the most common adverse effects were diarrhea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), swelling of nasal passages and throat (often due to catching the common cold) (17.0%), weakness (13.4%), itchiness (13.7%), joint pain (11.4%), nausea (12.7%), pain in an extremity (13.4%), back pain (12.1%) and cough (12.1%).
In clinical trials of the neoadjuvant use of the combination, more than 50% of people had hair loss and loss of neutrophils.
In both uses, more than 10% of people additionally experienced: loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, nail disease
A nail disease or onychosis is a disease or deformity of the nail. Although the nail is a structure produced by the skin and is a skin appendage, nail diseases have a distinct classification as they have their own signs and symptoms which may r ...
, and muscle pain.
Pharmacology
The metabolism of pertuzumab has not been directly studied; in general antibodies are cleared principally by catabolism
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
. The median clearance of pertuzumab was 0.235 liters/day and the median half-life was 18 days.
Mechanism of action
HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
is an extracellular receptor—a receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
- that when activated, sets off signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
through several pathways that stimulate cell proliferation and cell growth; if overexpressed it can cause uncontrollable growth. HER2 positive breast cancer is caused by ERBB2 gene amplification that results in overexpression of HER2 in approximately 15-30% of breast cancer tumors.
Like many receptors HER2 normally combines another protein in order to function (a process called dimerization); it can bind with a second HER2 receptor (acting as a homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
) and it can heterodimerize with a different receptor of the HER family. The most potent dimer for activating signalling pathways is HER2/HER3.[
The ]epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
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
Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wit ...
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
Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wit ...
and docetaxel in HER2-positive metastatic breast cancer. Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer later that year. Results of a Phase II trial in the neoadjuvant setting, NeoSphere, published in 2012, and results of a Phase II cardiac safety study in the same population, Tryphaena, published in 2013. The FDA approved the neoadjuvant indication in 2013.
Pertuzumab was approved for medical use in the European Union in 2013.
Society and culture
Economics
, in the US each cycle of the three-drug combination given every three weeks costs around , not including ancillary care costs.
In the UK, a NICE
Nice ( , ; Niçard: , classical norm, or , nonstandard, ; it, Nizza ; lij, Nissa; grc, Νίκαια; la, Nicaea) is the prefecture of the Alpes-Maritimes department in France. The Nice agglomeration extends far beyond the administrative c ...
evaluation in 2015, made a preliminary finding that the drug combination was not cost effective, and NICE rejected the drug in the neoadjuvant setting in May 2016, primarily because it was unknown if the drug combination provided a survival benefit. This decision was subsequently reversed six months later and pertuzumab became the first new breast cancer drug to be approved by NICE for routine NHS
The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
funding in almost a decade
after Roche pledged to provide the drug to the NHS at an undisclosed discount for patients in the neoadjuvant setting and to share the long–term financial risks.
References
Further reading
*
External links
*
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