Status: approved in India in mid-2005

Cross ref.: See the entries above for other EGFr monoclonal antibodies, e.g., Erbitux and Vectibix

Organizations involved:

Center of Molecular Immunology (CIM) – Manuf.; R&D; Tech.; Parent

CIMAB S.A. – Tech.

InnoMab PTE Ltd, – Tech.

InnoKeys PTE Ltd. – Tech.; USA mark.; Europe mark,; Parent

Biocon Biopharmaceuticals Ltd. - Former

Biocon Ltd. – Former; Parent

Innogene Kalbiotech – Former

University of Havana – Parent

YM BioSciences Inc. – Parent

CIMYM BioSciences Inc. – Former

Daiichi Sankyo Co., Ltd. –Japan mark.

Description: BIOMab EGFR is a formulation of nimotuzumab, a recombinant humanized IgG1 murine monoclonal antibody with specificity for human epidermal growth factor receptor (EGFr). Biocon describes agent drug as the first humanized anti-EGFR monoclonal antibody in the world (using this term, rather than chimeric or human).

Nimotuzumab was obtained by transplanting the complementarity determining regions (CDR) of the murine

IgG2a monoclonal ior egf/r3, to a human framework assisted by computer modeling. The parental murine monoclonal, egf/r3, was generated by fusing the murine myeloma cells SP2/Ag14 with splenocytes from Balb/c mice immunized with a purified human placenta fraction enriched in EGFr and not with EGFr purified from cultured cells.

Biological.: Studies have shown nimotuzumab mediates anti-tumur effects by its capacity to inhibit proliferation, survival and angiogenesis. In contrast to other anti-EGFR antibodies, the intrinsic properties of Nimotuzumab requires bivalent binding (i.e., binding with both antibody arms to two targets simultaneously) for stable attachment to cellular surfaces, which leads to Nimotuzumab selectively binding to cells that express moderate to high EGFr levels. When EGFr expression is low as on healthy tissues, Cetuximab and Panitumumab still have high avidity target binding because of their higher affinity constants. In contrast, since Nimotuzumab has lesser affinity and hence binds with less avidity, the target binding interaction is transient. Thus it spares healthy tissues and avoids severe dose limiting toxicities. When EGFr expression is moderate to high, all of these antibodies can bind with similar higher avidity. There is no clinical evidence with Panitumumab and Cetuximab that suggests higher affinity leads to greater efficacy, although stronger binding clearly leads to higher toxicities. The binding properties of Nimotuzumab may lead to improved in vivo targeting of EGFr-overexpressing tumors, as compared with the other antibodies.

Nomenclature; EGF Mab, rDNA [BIO]; nimotuzumab [INN]; BIOMab EGFR [TR India, assigned to Biocon]; immunoglobulin G1, anti-(humanized mouse monoclonal hR3 ß1 chain anti-human epidermal growth factor receptor), disulfide with humanized mouse monoclonal hR3 K-chain, dimer [CAS]; 828933-51-3 [CAS RN]; TheraCIM h-R3 [SY]; h-R3 [SY]

Companies.: BIOMab EGFR was originally developed by Biocon Biopharmaceuticals Ltd, a joint venture between Biocon Ltd. (Bangalore, India) and CIMAB SA (Centro de Investigaciones del Medio Ambiente y Biomedicina; Havana, Cuba), operating as a subsidiary of Biocon Ltd.. Biocon Pharmaceuticals has rights from CIMAB for the Indian subcontinent.

BIOMab EGFR was originally developed by the Center of Molecular Immunology (Centro de Inmunología Molecular; CIM; Havana, Cuba), a subsidiary of the University of Havana (with all of these organizations essentially part of the Cuban government). CIMAB is a subsidiary and commercially develops and licenses products from CIM. Innogene Kalbiotech later assumed control/ownership of Biocon's involvement with TheraCIM.

CIMAB has licensed nimotuzumab to CIMYM BioSciences Inc. for major market countries including Europe, North America, Japan and the Pacific Rim countries excluding China. CIMYM is a joint venture subsidiary 80% owned by YM BioSciences and 20% owned by CIMAB S.A. (representing Centro de Inmunología Molecular, Cuba).

CIMYM/YM BioSciences Inc. has (sub)licensed exclusive rights in Japan to Daiichi Sankyo Co., Ltd.

In May 2007, YM Biosciences reported that the facilities for manufacture of nimotuzumab had been scaled-up to 500 L continuous perfusion fermentation process. Nimotuzumab has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries.

In Dec. 2012, CIMYM BioSciences Inc. has sold its assets relating to nimotuzumab to InnoKeys PTE Ltd. (Singapore) including an immediate $2 million payment. CIMAB S.A. has partnered with InnoKeys and formed a joint venture called InnoMab PTE Ltd, which is now the owner of the assets related to nimotuzumab.

Status: On July 20, 2006, YM Biosciences received approval in India for the treatment of head & neck cancer.

In early 2009, nimotuzumab was approved 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; and for nasopharyngeal cancer in China (PRC). Approvals have also been granted in Thailand and Myanmar.

Nimotuzumab has been approved in China (PRC) for squamous cell nasopharyngeal carcinoma, based on a 75% improvement in the complete response rate (91% vs 52%) in patients treated with nimotuzumab plus radiotherapy versus radiotherapy alone.

Nimotuzumab has been granted Orphan Drug Status for glioma in USA and for glioma and pancreatic cancer in the Europe.

Trials: YM reports that in trials undertaken by Biocon Biopharmaceuticals Ltd to gain approval for nimotuzumab in India, “no cases were observed of the severe rash commonly produced by similar agents with the same target, consistent with previous study results. The absence of this debilitating side-effect should prove a key differentiator for nimotuzumab in the marketplace.” Note, YM refers to BIOMab EGFR being (bio)similar (generic, biogeneric, biosimilar, biocomparable, follow-on protein/biologic, etc.) relative to another ERFr mabs, presumably Erbitux and not Vectibix.

As reported in July 2006 (with the Indian approvals, nimotuzumab was in a Phase IIl trial in Europe in combination with radiation for the treatment of pediatric pontine glioma. YM BioSciences and CIMYM BioSciences Inc. were preparing to file for authorization to conduct a trial in North America in pediatric pontine glioma. YM was developing nimotuzumab for non-small cell lung cancer and pancreatic cancer and proposed to pursue clinical development in adult glioma, esophageal cancer and colorectal cancer. YM’s licensor, CIMAB SA and its parent, the Center of Molecular Immunology, were conducting trials with nimotuzumab in glioma, breast, esophageal, uterine cervix, prostate and head and neck cancers.

In April 2007, Daiichi Sankyo initiated a Phase I trial of nimotuzumab for the treatment of solid tumors.

In April 2007, YM Biosciences reported, “The development program for nimotuzumab includes ongoing studies in Pediatric Pontine Glioma, NSCLC, Head & Neck, Breast, Cervical, Prostate and Esophageal cancers. A trial in colorectal cancer in North America is currently in design.

Ref.: "Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin, by Ramakrishnan, M.S., et al., mAbs (Landes Bioscience), vol. 1, no. 1, p. 1-8

.