Matuzumab (formerly EMD 72000) is a

humanized monoclonal antibody Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal an ...

for the treatment of cancer. It binds to the

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor rece ...

(EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed at the Wistar Institute in Philadelphia, Pennsylvania Produced and developed by

Merck Serono Merck Serono (EMD Serono in the United States and Canada) is a pharmaceutical company headquartered in Darmstadt, Germany, and a brand and division of Merck focused on biopharmaceuticals. In September 2006, Merck KGaA announced its intent to p ...

in cooperation with

Takeda Pharmaceutical The is a Japanese multinational pharmaceutical company, with partial American and British roots. It is the largest pharmaceutical company in Asia and one of the top 20 largest pharmaceutical companies in the world by revenue (top 10 followin ...

, it has undergone

phase II clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

for the treatment of

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...

, 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.

Mechanism of action

Matuzumab binds to epidermal growth factor receptor (EGFR) on the outer membrane of normal and tumor cells. The matuzumab epitope has been mapped to domain III of the extracellular domain of the EGFR. The EGFR is receptor tyrosine kinase which binds multiple growth factors including EGF ( epidermal growth factor) and other members of the EGF family of

growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regul ...

s, resulting in activation of its tyrosine kinase activity. Activation of the EGFR has diverse effects on target cells depending on cell type and tissue context. It directs cell fate decision relating to cell growth, survival and, differentiation. Development of matuzumab and other antibodies to the EGFR (for example

cetuximab Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...

) as cancer therapeutics was motivated by observations that EGFR expression and/or signaling is frequently upregulated in cancer cells.

Preclinical and Clinical testing

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 (ASCO) 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 Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...

(NSCLC) patients. Some studies have shown a negative correlation between the effectiveness of EGFR

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

s and such mutations. The effect of matuzumab (in combination with

paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical canc ...

) does not seem to be dependent on these mutations.

Advanced adenocarcinomas of stomach and esophagus

Results of two studies regarding adenocarcinomas have shown matuzumab to be well tolerated in combination with two standard chemotherapies –

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...

and

leucovorin Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...

(PFL) as well as

epirubicin Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in ...

, cisplatin and

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Com ...

(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

intestinal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

due to negative results in phase II studies.

Discontinuation of development

No further clinical trials have been conducted since the phase I trial in 2007. On February 18, 2008, Takeda and Merck announced that they would no longer pursue the development of the drug.

References

{{Growth factor receptor modulators Monoclonal antibodies for tumors Merck brands