Matuzumab

Matuzumab ?
Monoclonal antibody
Type Whole antibody
Source Humanized
Target EGFR
Clinical data
Pregnancy cat.  ?
Legal status clinical development failed
Pharmacokinetic data
Bioavailability N/A
Identifiers
CAS number 339186-68-4 YesY
ATC code None
Chemical data
Formula  ?
 N(what is this?)  (verify)

Matuzumab (formerly EMD 72000) was a humanized 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,[1] esophageal and stomach cancer[2] 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.[3] In February 2008, the development was halted because of disappointing study results.[4]

Contents

Mechanism of action

The antibody is directed against EGFR, an enzyme found in cell membranes. This enzyme, a receptor tyrosine kinase, binds epidermal growth factor and other growth factors, 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).

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 ,[5]

After determining the pharmacokinetic characteristics in a phase I study,[6] 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:

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.[7]

On August 27, 2007 Merck announced that matuzumab will not be used for intestine cancer due to negative results in phase II studies.[3]

Discontinuation of development

No further clinical trials have been conducted since the phase I trial[7] in 2007. On February 18, 2008, Takeda and Merck announced that they would no longer pursue the development of the drug.[4][8]

References

  1. ^ ClinicalTrials.gov NCT00111839 Effects of Matuzumab in Combination With Pemetrexed for the Treatment of Advanced Lung Cancer
  2. ^ ClinicalTrials.gov NCT00215644 MATRIX EG (Matuzumab Treatment With ECX in Esophago-Gastric Cancer)
  3. ^ a b "Krebsmedikament floppt [Cancer drug flops]" (in German). n-tv. August 29, 2007. http://www.n-tv.de/845118.html. Retrieved August 27, 2007. 
  4. ^ a b "Merck KGaA stellt Entwicklung von Matuzumab ein [Merck KGaA discontinues development of matuzumab]" (in German). NewsVZ.de. February 18, 2008. http://www.newsvz.de/details_Boerse,DJ-Merck-KGaA-stellt-Entwicklung-von-Matuzumab-ein,329480.html. Retrieved January 5, 2010. 
  5. ^ Meira, D; Nobrega, I; Almeida, V; Mororo, J; Cardoso, A; Silva, R; Albano, R; Ferreira, C (2009). "Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway". European Journal of Cancer 45 (7): 1265–1273. doi:10.1016/j.ejca.2008.12.012. PMID 19167213. 
  6. ^ Vanhoefer, U; Tewes, M; Rojo, F; Dirsch, O; Schleucher, N; Rosen, O; Tillner, J; Kovar, A et al. (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 22 (1): 175–84. doi:10.1200/JCO.2004.05.114. PMID 14701780. 
  7. ^ a b Rao, S; Starling, N; Cunningham, D; Benson, M; Wotherspoon, A; Lüpfert, C; Kurek, R; Oates, J et al. (2008). "Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer". British journal of cancer 99 (6): 868–74. doi:10.1038/sj.bjc.6604622. PMC 2538760. PMID 19238629. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2538760. 
  8. ^ "Takeda Discontinues Development of Matuzumab". Takeda Pharmaceutical Co., Ltd.. February 18, 2008. http://www.takeda.com/press/article_29042.html. Retrieved January 5, 2010.