Nimotuzumab

Nimotuzumab (BIOMAb EGFR, Biocon, India^[2]; Theracim, YM Biosciences, Cuba; Theraloc, Oncosciences, Europe) is a chimeric monoclonal antibody used to treat squamous cell carcinomas of the head and neck, nasopharyngeal cancer and glioma.

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.

Most monoclonal antibodies are originally created by mouse cells, but this can cause an immune reaction to mouse proteins. Chimeric antibodies are made using parts of mouse proteins and parts of human proteins, which causes less of an immune reaction. Nimotuzumab contains 95% human antibody sequences. This reduces adverse effects such as rash, diarrhea and conjunctivitis.^{[citation needed]}

Mechanism

Nimotuzumab binds with optimal affinity and high specificity to the extracellular region of EGFR (epithelial growth factor receptor). This results in a blockade of ligand binding and receptor activation.^[1][3] 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.^[4] The Center of molecular immunology with YM Biosciences and its licensees are committed to the clinical development and subsequent marketing of nimotuzumab. These include Daiichi-Sankyo Co. Ltd. in Japan, Oncoscience AG in Europe, Kuhnil Pharmaceutical Co., Ltd. in South Korea and Innogene Kalbiotech Pte Ltd. in South East Asia. In addition, as of November 30, 2007 eight other companies around the globe were involved in a consortium with CIM and YM or with their licensees, or unilaterally in a number of trials in multiple indications. Other licensees for nimotuzumab include Biocon BioPharmaceuticals Ltd. (BBPL) in India, Biotech Pharmceutical Co. Ltd. in China, Delta Laboratories in Colombia, Eske Group in Peru, Eurofarma Laboratorios Ltda. in Brazil, Ferozsons Labs in Pakistan, Laboratorio Elea S.A.C.I.F.yA. in Argentina and Laboratorios PiSA in Mexico.

Nimotuzumab has been administered to >2,000 patients worldwide through commercial sales and is currently in a phase II clinical trial in United States and Canada due to end in mid 2010^[5].

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.^[3]

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:

• Chills
• Fever
• Nausea and vomiting
• Dryness of mouth
• Asthenia
• Hypertension/hypotension
• Flushing

All adverse events were mild to moderate and were considered infusion reactions. No patient developed acneiform rash or other dermatological toxicity.^[6] Grade 3 somnolence was reported in one patient following a 400 mg dose of nimotuzumab.^[7]

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%).^[8]

These adverse reactions respond to treatment with conventional doses of analgesic and antihistaminics.^[9]

Notes

1. ^ ^{a b} Investigator Brochure. TheraCIM h-R3 (YMB1000). YM BioSciences Inc. Mississauga: ON. 2005
2. ^ BIOMAb EGFR(Biocon, India)
3. ^ ^{a b} Ramos TC, Parada AC, Escobar NI. h-R3. Drugs Future. 2003;28(suppl 9):847-853
4. ^ 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
5. ^ http://clinicaltrials.gov/ct2/show/NCT00600054
6. ^ 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
7. ^ Crombet TR, Osorio M, Cruz T, et al. Use of humanized anti-epidermal growth factor receptor monoclonal antobody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol.2004;22:1-9
8. ^ Guozhen X, Li G. Phase II trial of recombinant humanized anti-human epidermal growth fator receptor monoclonal antibody (h-R3). Tumour hospital, China Academy of Medical Science. 2004:1-72
9. ^ TheraCIM h-R3 [package insert]. Havana City, Cuba: CIMAB S.A.