Nimotuzumab

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Nimotuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetEGFR
Clinical data
Routes of
administration		Intravenous
ATC code
Pharmacokinetic data
Elimination half-life62–304 hours
Identifiers
CAS Number
ChemSpider
Chemical and physical data
FormulaC6566H10082N1746O2056S40[1]
Molar mass[cannot calculate]Expression error: Unexpected < operator
 ☒NcheckY (what is this?)  (verify)

Nimotuzumab (h-R3,[2] BIOMAb EGFR, Biocon, India;[3] TheraCIM, CIMYM Biosciences, Canada; Theraloc, Oncoscience, Europe, CIMAher, Center of Molecular Immunology, Havana, Cuba) is a humanized monoclonal antibody that as of 2014 had orphan status in the US and EU for glioma, and marketing approval in India, China, and other countries for squamous cell carcinomas of the head and neck, and was undergoing several clinical trials.

Like cetuximab, nimotuzumab binds to the epidermal growth factor receptor (EGFR), a signalling protein that normally controls cell division. In some cancers, this receptor is altered to cause uncontrolled cell division, a hallmark of cancer. These monoclonal antibodies block EGFR and stop the uncontrolled cell division.

It has a chimeric human-mouse h-R3 heavy chain and a human-mouse h-R3 κ-chain.[4][1]

Mechanism

Nimotuzumab binds with optimal affinity and high specificity to the extracellular region of EGFR (epidermal growth factor receptor). This results in a blockade of ligand binding and receptor activation.[5] Epidermal growth factor receptor (EGFR) is a key target in the development of cancer therapeutics. EGFR-targeting drugs have been shown to improve response when used with conventional treatments such as radiation therapy and chemotherapy.

Development status

It was developed at the Center of molecular immunology (CIM) in Havana, Cuba.[6] CIM's commercialization, arm, CIMAB S.A. formed a joint venture with YM Biosciences called CIMYM BioSciences in 1995 that was 80% owned by YM and 20% owned by CIMAB.[7]

CIMYM BioSciences licensed European rights to nimotuzumab to Oncoscience AG in 2003, the South Korean rights to Kuhnil Pharmaceutical Co., Ltd. in 2005, and in 2006, licensed the Japanese rights to [Daiichi Sankyo]] and rights to certain countries in Asia and Africa to Innogene Kalbiotech Pte Ltd.[7] Other licensees for nimotuzumab include Biocon BioPharmaceuticals Ltd. (BBPL) in India, Biotech Pharmaceutical Co. Ltd. in China, Delta Laboratories in Colombia, European Chemicals SAC – Corporación Infarmasa SA in Peru, Eurofarma Laboratorios Ltda. in Brazil, Ferozsons Labs in Pakistan, Laboratorio Elea S.A.C.I.F.yA. in Argentina, EL KENDI Pharmaceutical in Algeria and Laboratorios PiSA in Mexico.[citation needed]

In December 2012, CIMYM BioSciences dissolved and sold its assets related to nimotuzumab to InnoKeys PTE Ltd.[8]

According to a 2009 review: "Nimotuzumab was approved for the following indications—For squamous cell carcinoma in head and neck (SCCHN) in India, Cuba, Argentina, Colombia, Ivory Coast, Gabon, Ukraine, Peru and Sri Lanka; for glioma (pediatric and adult) in Cuba, Argentina, Philippines and Ukraine; for nasopharyngeal cancer in China. It has been granted orphan drug status for glioma in USA and for glioma and pancreatic cancer in Europe."[2]

As of 2014 Nimotuzumab was in additional Phase I and II clinical trials.[9]

Safety

The toxicity and safety of nimotuzumab have been assessed in several pre-clinical and clinical studies wherein it was noticed that side effects such as hypomagnesemia and debilitating skin rashes were absent in patients treated with Nimotuzumab . Classical EGFR inhibition related side effects were also negligible. The improved safety results without compromising on efficacy can be attributed to its unique molecular profile[clarification needed].

Safety in pre-clinical experiments

  • Nimotuzumab did not produce any significant acute toxicity following single administration of up to 10 times the dose proposed for clinical trials.
  • No treatment-related systemic toxicity was observed in animals after administering nimotuzumab once daily for 14 days.[5]

Safety profile in clinical trials

Nimotuzumab has been found to be very well tolerated in clinical trials. Common adverse reactions seen in patients treated with nimotuzumab include:

All adverse events were mild to moderate and were considered infusion reactions. No patient developed acneiform rash or other dermatological toxicity.[10] Grade 3 somnolence was reported in one patient following a 400 mg dose of nimotuzumab.[11]

In a phase II trial, the most common adverse reactions were fever (4.28%), dizziness and hypotension (2.86%) and mild skin rash (1.43%).[12]

Notes

  1. ^ a b WHO Drug Information, Vol. 19, No. 4, 2005 Proposed INN List 94, p.333
  2. ^ a b Ramakrishnan, Melarkode S. (2009). "Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin". mAbs. 1 (1): 41–48. doi:10.4161/mabs.1.1.7509. PMID 20046573. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ BIOMAb EGFR (Biocon, India)
  4. ^ Merck Index 14th Edition Monograph number 10585.
  5. ^ a b Ramos TC, Parada AC, Escobar NI. h-R3. Drugs Future. 2003;28(suppl 9):847-853
  6. ^ Mateo C, Moreno E, Amour K, Lombardero J, Harris W, Pérez R. Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: Recovery of antagonistic activity. Immunotechnology 1997;3:71-81
  7. ^ a b YM Biosciences YM Biosciences Annual Report for year ended June 30, 2007
  8. ^ YM Biosciences press release. December 2012 YM BioSciences Reports Divestiture of Nimotuzumab Assets by CIMYM
  9. ^ Vacchelli E et al. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology. 2014 Jan 1;3(1):e27048. PMID 24605265
  10. ^ Crombet T, Torres L, Neninger E, et al. Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer. J Immunother.2003;26:139-148
  11. ^ Crombet TR, Osorio M, Cruz T, et al. Use of humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol.2004;22:1-9
  12. ^ Guozhen X, Li G. Phase II trial of recombinant humanized anti-human epidermal growth factor receptor monoclonal antibody (h-R3). Tumour hospital, China Academy of Medical Science. 2004:1-72
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