Matuzumab
Encyclopedia
Matuzumab was a humanize
d monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor
(EGFR) with high affinity.
Developed by Merck Serono
in cooperation with Takeda Pharmaceutical, it has undergone phase II clinical trials for the treatment of colorectal
, lung
, esophageal
and stomach cancer
early in the 2000s. In August 2007, Merck Serono announced that the preliminary results of the colorectal cancer study were less than promising, and that further trials for treating this type of cancer may be abandoned. In February 2008, the development was halted because of disappointing study results.
found in cell membrane
s. This enzyme, a receptor tyrosine kinase
, binds epidermal growth factor
and other growth factor
s, resulting in enzymatic (tyrosine kinase) activity. Via several intermediate steps, this leads to DNA synthesis
inside the cell and to cell proliferation. Cancer cells often have more EGFR molecules as normal cells. 80% of intestine cancer cells, for example, over-express
EGFR.
Matuzumab inhibits activation of the enzyme, and so the signal downstream is impaired. This should decrease invasion of the tumor cells into healthy tissue and propagation of the tumor into new body regions (forming of metastases).
After determining the pharmacokinetic characteristics in a phase I study, several phase II studies investigating the treatment of advanced stomach carcinoma were conducted.
At the conference of the American Society of Clinical Oncology
(CASCO) in May 2005, the following results from clinical phase II studies with matuzumab were presented:
) does not seem to be dependent on these mutations.
s have shown matuzumab to be well tolerated in combination with two standard chemotherapies – cisplatin
, 5-fluorouracil and leucovorin (PFL) as well as epirubicin
, cisplatin and capecitabine (ECX) – as a first line therapy. Rates of response
were up to 53% with a combination of matuzumab and ECX.
On August 27, 2007 Merck announced that matuzumab will not be used for intestine cancer due to negative results in phase II studies.
Humanize
Humanize may refer to:*Humanize a 2001 album by the British jazz/funk band Big Boss Man*Humanized antibody, a type of monoclonal antibody...
d monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) with high affinity.
Developed by Merck Serono
Merck Serono
Merck Serono is a pharmaceutical company headquartered in Geneva, Switzerland. In September 2006, Merck KGaA announced its intent to purchase the majority of Serono shares from Ernesto Bertarelli and the Bertarelli family. The Merck-Serono merger was announced on September 21, 2006...
in cooperation with Takeda Pharmaceutical, it has undergone phase II clinical trials for the treatment of colorectal
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, lung
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, esophageal
Esophageal cancer
Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily squamous cell cancer and adenocarcinoma . Squamous cell cancer arises from the cells that line the upper part of the esophagus...
and stomach cancer
Stomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
early in the 2000s. In August 2007, Merck Serono announced that the preliminary results of the colorectal cancer study were less than promising, and that further trials for treating this type of cancer may be abandoned. In February 2008, the development was halted because of disappointing study results.
Mechanism of action
The antibody is directed against EGFR, an enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
found in cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s. This enzyme, a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s 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 kinase proteins....
, binds epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
and other growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s, resulting in enzymatic (tyrosine kinase) activity. Via several intermediate steps, this leads to DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
inside the cell and to cell proliferation. Cancer cells often have more EGFR molecules as normal cells. 80% of intestine cancer cells, for example, over-express
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
EGFR.
Matuzumab inhibits activation of the enzyme, and so the signal downstream is impaired. This should decrease invasion of the tumor cells into healthy tissue and propagation of the tumor into new body regions (forming of metastases).
Preclinical and Clinical testing
An important preclinical study showed that even though matuzumab efficiently binds EGFR and blocks its phosphorylation, it is not as effective as cetuximab (a chimeric anti-EGFR MAb)in inhibiting A431 cell proliferation as it fails to inhibit the MAPK pathway. However, the combination of MAbs synergistically reduced A431 cell proliferation, due to down-regulation of EGFR and inhibition of AKT and MAPK phosphorylation. Taken together, the data indicated that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival in vitro ,After determining the pharmacokinetic characteristics in a phase I study, several phase II studies investigating the treatment of advanced stomach carcinoma were conducted.
At the conference of the American Society of Clinical Oncology
American Society of Clinical Oncology
The American Society of Clinical Oncology is the world's leading professional organization representing physicians of all oncology subspecialties who care for people with cancer. Founded in 1964 by Drs...
(CASCO) in May 2005, the following results from clinical phase II studies with matuzumab were presented:
Advanced non-smallcellular lung carcinoma
Mutations in the kinase domain of the EGFR are observed with approximately 2 to 25% of non-small cell lung carcinoma (NSCLC) patients. Some studies have shown a negative correlation between the effectiveness of EGFR tyrosine kinase inhibitors and such mutations. The effect of matuzumab (in combination with paclitaxelPaclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
) does not seem to be dependent on these mutations.
Advanced adenocarcinomas of stomach and esophagus
Results of two studies regarding adenocarcinomaAdenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
s have shown matuzumab to be well tolerated in combination with two standard chemotherapies – cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, 5-fluorouracil and leucovorin (PFL) as well as epirubicin
Epirubicin
Epirubicin is an anthracycline drug used for chemotherapy. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere....
, cisplatin and capecitabine (ECX) – as a first line therapy. Rates of response
Rate of response
Rate of response is a ratio between two measurements with different units. Rate of responding is the number of responses per minute, or some other time unit. It is usually written as R. Its first major exponent was B.F. Skinner . It is used in the Matching Law.R = # of Responses/Unit of time =...
were up to 53% with a combination of matuzumab and ECX.
On August 27, 2007 Merck announced that matuzumab will not be used for intestine cancer due to negative results in phase II studies.