Matuzumab

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 factors, 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) 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 (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 paclitaxel) 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, 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 intestinal cancer 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

References

1. (February 1987). "Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide". Archives of Biochemistry and Biophysics.
2. (July 1987). "Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects". Cancer Research.
3. {{ClinicalTrialsGov. NCT00111839. Effects of Matuzumab in Combination With Pemetrexed for the Treatment of Advanced Lung Cancer
4. {{ClinicalTrialsGov. NCT00215644. MATRIX EG (Matuzumab Treatment With ECX in Esophago-Gastric Cancer)
5. (August 29, 2007). "Krebsmedikament floppt". [[n-tv]].
6. (April 2008). "A molecular view of anti-ErbB monoclonal antibody therapy". Cancer Cell.
7. (May 2008). "Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425". Cancer Biology & Therapy.
8. (January 2004). "Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor". Journal of Clinical Oncology.
9. (September 2008). "Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer". British Journal of Cancer.
10. (February 18, 2008). "Merck KGaA stellt Entwicklung von Matuzumab ein". NewsVZ.de.
11. (February 18, 2008). "Takeda Discontinues Development of Matuzumab". Takeda Pharmaceutical Co., Ltd..