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.
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. 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.[2]
Development status
It was developed at the Center of molecular immunology (CIM) in Havana, Cuba.[5] 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.[6]
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.[6] Other licensees for nimotuzumab include Biocon BioPharmaceuticals Ltd. (BBPL) in India, Biotech Pharmaceutical Co. Ltd. in China, Delta Laboratories in Colombia, European Chemicals SAC, Quality Pharma 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.[7]
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 (expired now); 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.[8]
In April 2014, Daiichi Sankyo announced that it was halting a multicenter, randomized, double-blind, placebo-controlled Phase III study investigating nimotuzumab for first-line therapy in patients with unresectable and locally advanced squamous cell lung cancer, due to safety issues in certain patients who received a combination of cisplatin, vinorelbine, radiotherapy, and nimotuzumab.[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 usually caused by EGFR inhibitors, especially rashes and other skin toxicities, were negligible. Scientists have hypothesized that this is because nimotuzumab binds only to cells that express moderate to high EGFR levels.[2]
Nimotuzumab has been found to be very well tolerated in clinical trials. Common adverse reactions seen in patients treated with nimotuzumab include:[10][11]
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.
Biocon Limited is an Indian biopharmaceutical company that is based in Bangalore, India. It was founded by Kiran Mazumdar-Shaw in 1978. The company manufactures generic active pharmaceutical ingredients (APIs) that are sold in approximately 120 countries, including the United States and Europe. It also manufactures novel biologics as well as biosimilar insulins and antibodies, which are sold in India as branded formulations. Biocon's biosimilar products are also sold in both bulk and formulation forms in several emerging markets. Syngene International Limited (Syngene) is a publicly listed subsidiary of Biocon, operating in the contract research services space.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
The Center of Molecular Immunology or CIM, is a cancer research institution located on the west side of Havana, Cuba. 23.0755°N 82.4708°W Opened on December 5, 1994, it focuses on the research and production of new biopharmaceutical products for the treatment of cancer and other nontransmissible diseases.
Daiichi Sankyo Company, Limited is a global pharmaceutical company and the second-largest pharmaceutical company in Japan. It achieved JPY 981.8 billion in revenue in 2019. The company owns the American biotechnology company Plexxikon, American pharmaceutical company American Regent, German biotechnology company U3 Pharma, and recently sold Ranbaxy Laboratories in India. Daiichi Sankyo Co., Ltd. is the producer of Benicar (Olmesartan), an angiotensin II receptor antagonist and top selling drug in the U.S. Global sales of Olmesartan in 2013 were 300.2 billion yen.
Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.
Matuzumab is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed at the Wistar Institute in Philadelphia, Pennsylvania
Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma of the head and neck (SCCHN), a type of cancer.
Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
Necitumumab (INN) is a recombinant human IgG1 monoclonal antibody used as an antineoplastic, which is manufactured by Eli Lilly. It binds to the epidermal growth factor receptor (EGFR). The US FDA approved necitumumab under the brand name Portrazza for use with gemcitabine and cisplatin in previously untreated metastatic squamous non-small-cell lung carcinoma (NSCLC). It was counterproductive in non-squamous non-small-cell lung carcinoma.
Symphogen is a biotechnology company located in Copenhagen, Denmark that develops protein drugs based on recombinant monoclonal antibody mixtures. These drugs are different from the polyclonal antibodies, as each antibody in the mixture is produced from one carefully selected clone. Their three main areas of therapeutic research are immunoglobulin replacement, cancer, and infectious diseases. The company was founded in 2000 and has patents on a drug discovery platform called Symplex and a drug manufacturing platform called Sympress. By 2009, ten drugs were being developed with rozrolimupab (Sym001) being the lead product. Laboratoires Servier acquired Symphogen in 2020.
John Mendelsohn was a president of the University of Texas MD Anderson Cancer Center in Houston. He was an internationally recognized leader in cancer research.
Ficlatuzumab is a humanized monoclonal antibody designed for the treatment of cancers.
CimaVax-EGF is a vaccine used to treat cancer, specifically non-small-cell lung carcinoma (NSCLC). CIMAvax-EGF is composed of recombinant human epidermal growth factor (EGF) conjugated to a protein carrier.
Demcizumab is a humanized monoclonal antibody which is used to treat patients with pancreatic cancer or non-small cell lung cancer. Demcizumab has completed phase 1 trials and is currently undergoing phase 2 trials. Demcizumab was developed by OncoMed Pharmaceuticals in collaboration with Celgene.
Lirilumab (INN) is a human monoclonal antibody designed for the treatment of cancer. It binds to KIR2DL1/2L3.
YM BioSciences Inc. was a Canadian drug development company primarily focused on advancing CYT-387, an orally administered inhibitor of both the JAK1 and JAK2 kinases, which have been implicated in a number of hematological and immune cell disorders including myeloproliferative neoplasms and inflammatory diseases as well as certain cancers. YM BioSciences also had several preclinical programs underway with candidates from its library of compounds identified through internal research conducted at YM BioSciences Australia.
Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.
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