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Matuzumab

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Matuzumab

Matuzumab?
Monoclonal antibody
Type Whole antibody
Source Humanized
Target EGFR
Clinical data
Legal status
  • clinical development failed
Pharmacokinetic data
Bioavailability N/A
Identifiers
CAS Registry Number  N
ATC code None
 N   

Matuzumab (formerly EMD 72000) is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity.[1] The mouse monoclonal antibody (mAb425) from which matuzumab was derived was developed at the Wistar Institute in Philadelphia, Pennsylvania [2]

Produced and developed by Merck Serono in cooperation with Takeda Pharmaceutical, it has undergone phase II clinical trials for the treatment of colorectal, lung,[3] esophageal and stomach cancer[4] 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.[5] In February 2008, the development was halted because of disappointing study results.[6]

Contents

  • Mechanism of action 1
  • Preclinical and Clinical testing 2
    • Advanced non-smallcellular lung carcinoma 2.1
    • Advanced adenocarcinomas of stomach and esophagus 2.2
  • Discontinuation of development 3
  • References 4

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.[7][8] 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,[9] 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.[10]

On August 27, 2007 Merck announced that matuzumab will not be used for intestinal cancer due to negative results in phase II studies.[5]

Discontinuation of development

No further clinical trials have been conducted since the phase I trial[10] in 2007. On February 18, 2008, Takeda and Merck announced that they would no longer pursue the development of the drug.[6][11]

References

  1. ^ Murthy, U.; Basu, A; Rodeck, U.; Herlyn, M.; Ross, A.H.; Das, M. (1987). "Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide". Arch Biochem Biophys 252 (2): 549–60.  
  2. ^ Rodeck, U.; Herlyn, M.; Herlyn, D.; Molthoff, C.; Atkinson, B.; Varello, M.; Steplewski, Z.; Koprowski, H. (1987). "Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects.". Cancer Research 47 (14): 3692–6.  
  3. ^ Clinical trial number NCT00111839 for "Effects of Matuzumab in Combination With Pemetrexed for the Treatment of Advanced Lung Cancer" at ClinicalTrials.gov
  4. ^ Clinical trial number NCT00215644 for "MATRIX EG (Matuzumab Treatment With ECX in Esophago-Gastric Cancer)" at ClinicalTrials.gov
  5. ^ a b "Krebsmedikament floppt" [Cancer drug flops] (in German).  
  6. ^ a b "Merck KGaA stellt Entwicklung von Matuzumab ein" [Merck KGaA discontinues development of matuzumab] (in German). NewsVZ.de. February 18, 2008. Retrieved January 5, 2010. 
  7. ^ Schmiedel, J.; Blaukat, A.; Li, S.; Knochel, T.; Ferguson, K.M. (2008). "A molecular view of anti-ErbB monoclonal antibody therapy.". Cancer Cell 13 (4): 365–73.  
  8. ^ Kamat, V.; Donaldson, J.M, Kari, C., Quadros, M.,R.,D., Lelkes, P.I., Chaiken, I., Cocklin, S., Williams, J.C., Papazoglou, E., Rodeck, U. (2008). "Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425.". Cancer Biology & Therapy 7 (5): 726–33.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ "Takeda Discontinues Development of Matuzumab". Takeda Pharmaceutical Co., Ltd. February 18, 2008. Retrieved January 5, 2010. 
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